2-phenanthridinyl carbaphenem antibacterial agent

ABSTRACT

The present invention relates to antibacterial agents of the carbapenem class, in which the 2-position sidechain is characterized by a phenanthridine moiety typically having a substituent attached to the nitrogen of the phenanthridine and substituted at other positions by various neutral substituents. When there is substitution on the nitrogen of the phenathridine moiety that nitrogen is a charged quaternary nitrogen.

BACKGROUND OF THE INVENTION

The present invention relates to antibacterial agents of the carbapenemclass, in which the 2-position sidechain is characterized by aphenanthridine moiety having a substituent on the nitrogen andsubstituted by various neutral substituents, as described in more detailfurther below.

Thienamycin was an early carbapenem antibacterial agent having a broadspectrum; it has the following formula: ##STR1## Later, N-formimidoylthienamycin was discovered; it has the formula: ##STR2##

The 2-phenanthridinyl-carbapenems of the present invention are notcharacterized by an antibacterial spectrum such as that of thienamycinor N-formimidoyl thienamycin. Rather, their spectrum of activityincludes gram positive microorganisms, especially methicillin resistantStaphylococcus aureus (MRSA), methicillin resistant Staphylococcusepidermidis (MRSE), and methicillin resistant coagulase negativeStapphylococci (MRCNS). The antibacterial compounds of the presentinvention thus comprise an important contribution to therapy of thesedifficult to control pathogens. Moreover, there is an increasing needfor agents effective against such pathogens (MRSA/MRCNS) which are atthe same time safe, i.e., free from undesirable toxic side effects. Noβ-lactam antibacterial has yet been found which meets theserequirements. And, the current agent of choice, vancomycin, aglycopeptide antibacterial, is experiencing an ever increasing amount ofresistance in the MRSA/MRCNS pathogens.

More recently, carbapenem antibacterial agents have been described whichhave a 2-substituent which is an aryl moiety optionally substituted by,e.g., aminomethyl and substituted aminomethyl. These agents aredescribed in U.S. Pat. Nos. 4,543,257 and 4,260,627 and have theformula: ##STR3##

However, there is no description or suggestion of a phenanthridinyl2-substituent such as characterizes the compounds of the presentinvention, nor is there any suggestion of the surprisingly betteranti-MRSA/MRCNS activity of the compounds of the present invention.

EP-A-0277 743 describes a particular class of compounds of the formula:##STR4## but this limited teaching in no way suggests the totallydifferent compounds of the present invention, nor their surprisinglybetter anti-MRSA/MRCNS activity.

SUMMARY OF THE INVENTION

The present invention provides novel carbapenem compounds of theformula: ##STR5## wherein Y is ##STR6## R is H or CH_(3;) R¹ and R² areindependently H, CH₃ --, CH₃ CH₂ --, (CH₃)₂ CH--, HOCH₂ --, CH₃CH(OH)--, (CH₃)₂ C(OH)--, FCH₂ CH(OH)--, F₂ CHCH(OH)--, F₃ CCH(OH)--,CH₃ CH(F)--, CH₃ CF₂ --, or (CH₃)₂ C(F)--;

R^(a) are independently selected from the group consisting of hydrogenand the radicals set out below, provided that not more than four R^(a)radicals are other than hydrogen:

a) a trifluoromethyl group: --CF₃ ;

b) a halogen atom: --Br, --Cl, --F, or --I;

c) C₁ -C₄ alkoxy radical: --OC₁₋₄ alkyl, wherein the alkyl is optionallymono-substituted by R^(q), where

R^(q) is a member selected from the group consisting of --OH, --OCH₃,--CN, --C(O)NH₂, --OC(O)NH₂, CHO, --OC(O)N(CH₃)₂, --SO₂ NH₂, --SO₂N(CH₃)₂, --SOCH₃, --SO₂ CH₃, --F, --CH₃, --COOM^(a) (where M^(a) ishydrogen, alkali metal, methyl or phenyl), tetrazolyl (where the pointof attachment is the carbon atom of the tetrazole ring and one of thenitrogen atoms is mono-substituted by M^(a) as defined above) and --SO₃M^(b) (where M^(b) is hydrogen or an alkali metal);

d) a hydroxy group: --OH;

e) a carbonyloxy radical: --O(C═O)R^(s), where

R^(s) is C₁₋₄ alkyl or phenyl, each of which is optionallymono-substituted by R^(q) as defined above;

f) a carbamoyloxy radical: --O(C═O)N(R^(y))R^(z) where R^(y) and R^(z)are independently H, C₁₋₄ alkyl (optionally mono-substituted by R^(q) asdefined above), together a 3- to 5-membered alkylidene radical to form aring (optionally substituted with R^(q) as defined above) or together a2- to 4-membered alkylidene radical, interrupted by --O--, --S--,--S(O)-- or --S(O)₂ -- to form a ring (where the ring is optionallymono-substituted with Rq as defined above);

g) a sulfur radical: --S(O)_(n) --R^(s) where n=0-2, and R^(s) isdefined above;

h) a sulfamoyl group: --SO₂ N(R^(y))R^(z) where R^(y) and R^(z) are asdefined above;

i) azido: N₃

j) a formamido group: --N(R^(t))(C═O)H, where

R^(t) is H or C₁₋₄ alkyl, and the alkyl thereof is optionallymono-substituted by R^(q) as defined above;

k) a (C₁ -C₄ alkyl)carbonylamino radical: --N(R^(t))(C═O)C₁₋₄ alkyl,where R^(t) is as defined above, and the alkyl group is also optionallymono-substituted by R^(q) as defined above;

1) a (C₁ -C₄ alkoxy) carbonylamino radical: --N(R^(t))(C═O)OC₁₋₄ alkyl,where R^(t) is as defined above, and the alkyl group is also optionallymono-substituted by R^(q) as defined above;

m) a ureido group: --N(R^(t))(C═O)N(R^(y))R^(z) where R^(t), R^(y) andR^(z) are as defined above;

n) a sulfonamido group: --N(R^(t))SO₂ R_(s), where R^(s) and R^(t) areas defined above;

o) a cyano group: --CN;

p) a formyl or acetalized formyl radical: --(C═O)H or --CH(OCH₃)₂ ;

q) (C₁ -C₄ alkyl)carbonyl radical wherein the carbonyl is acetalized:--C(OCH₃)₂ C₁₋₄ alkyl, where the alkyl is optionally mono-substituted byR^(q) as defined above;

r) carbonyl radical: --(C═O)R^(s), where R^(s) is as defined above;

s) a hydroximinomethyl radical in which the oxygen or carbon atom isoptionally substituted by a C₁ -C₄ alkyl group: --(C═NOR^(z))R^(y) whereR^(y) and R^(z) are as defined above, except they may not be joinedtogether to form a ring;

t) a (C₁ -C₄ alkoxy)carbonyl radical: --(C═O)OC₁₋₄ alkyl, where thealkyl is optionally mono-substituted by R^(q) as defined above;

u) a carbamoyl radical: --(C═O)N(R^(y))R^(z) where R^(y) and R^(z) areas defined above;

v) an N-hydroxycarbamoyl or N(C₁ -C₄ alkoxy)carbamoyl radical in whichthe nitrogen atom may be additionally substituted by a C₁ -C₄ alkylgroup: --(C═O)--N(OR^(y))R^(z) where R^(y) and R^(z) are as definedabove, except they may not be joined together to form a ring;

w) a thiocarbamoyl group: --(C═S)N(R^(y))(R^(z)) where R^(y) and R^(z)are as defined above;

x) carboxyl: --COOM^(b), where M^(b) is as defined above;

y) thiocyanate: --SCN;

z) trifluoromethylthio: --SCF₃ ;

aa) tetrazolyl, where the point of attachment is the carbon atom of thetetrazole ring and one of the nitrogen atoms is mono-substituted byhydrogen, an alkali metal or a C₁ -C₄ alkyl optionally substituted byR^(q) as defined above;

ab) an anionic function selected from the group consisting of: phosphono[P═O(OM^(b))₂ ]; alkylphosphono {P═O(OM^(b))-[O(C₁ -C₄ alkyl)]};alkylphosphinyl [P═O(OM^(b))-(C₁ -C₄ alkyl)]; phosphoramido[P═O(OM^(b))N(R^(y))R^(z) and P═O(OM^(b))NHR^(x) ]; sulfino (SO₂ M^(b));sulfo (SO₃ M^(b)); acylsulfonamides selected from the structuresCONM^(b) SO₂ R^(x), CONM^(b) SO₂ N(R^(y))R^(z), SO₂ NM^(b)CON(R^(y))R^(z) ; and SO₂ NM^(b) CN, where

R^(x) is phenyl or heteroaryl, where heteroaryl is a monocyclic aromatichydrocarbon group having 5 or 6 ring atoms, in which a carbon atom isthe point of attachment, in which one of the carbon atoms has beenreplaced by a nitrogen atom, in which one additional carbon atom isoptionally replaced by a heteroatom selected from O or S, and in whichfrom 1 to 2 additional carbon atoms are optionally replaced by anitrogen heteroatom, and where the phenyl and heteroaryl are optionallymono-substituted by R^(q), as defined above; M^(b) is as defined above;and R^(y) and R^(z) are as defined above;

ac) C₅ -C₇ cycloalkyl group in which one of the carbon atoms in the ringis replaced by a heteroatom selected from O, S, NH or N(C₁ -C₄ alkyl)and in which one additional carbon atom may be replaced by NH or N(C₁-C₄ alkyl), and in which at least one carbon atom adjacent to eachnitrogen heteroatom has both of its attached hydrogen atoms replaced byone oxygen thus forming a carbonyl moiety and there are one or twocarbonyl moieties present in the ring;

ad) C₂ -C₄ alkenyl radical, optionally mono-substituted by one of thesubstituents a) to ac) above and phenyl which is optionally substitutedby R^(q) as defined above;

ae) C₂ -C₄ alkynyl radical, optionally mono-substituted by one of thesubstituents a) to ac) above;

af) C₁ -C₄ alkyl radical;

ag) C₁ -C₄ alkyl mono-substituted by one of the substituents a)-ac)above;

ah) a 2-oxazolidinonyl moiety in which the point of attachment is thenitrogen atom of the oxazolidinone ring, the ring oxygen atom isoptionally replaced by a heteroatom selected from --S-- and NR^(t)(where R^(t) is as defined above) and one of the saturated carbon atomsof the oxazolidinone ring is optionally mono-substituted by one of thesubstituents a) to ag) above;

ai) an amine group: --NR^(e) R^(f), where

R^(e) and R^(f) are independently H, C₁₋₄ alkyl (optionallymono-substituted by R^(q) as defined above), together a 4- to 5-memberedalkylidene radical to form a ring (optionally substituted with R^(q) asdefined above);

R^(c) is selected from the group consisting of hydrogen and the radicalsset out below:

ba) C₁ -C₄ alkyl radical;

bb) C₁ -C₄ alkyl mono-substituted by one of the substituents a)-ac)described hereinabove;

bc) C₁ -C₄ alkoxy radical: --OC₁₋₄ alkyl, wherein the alkyl isoptionally mono-substituted by R^(q), where R^(q) is as describedhereinabove; and

bd) an amine group: --NR^(g) R^(h), where

R^(g) and R^(h) are independently H, C₁₋₄ alkyl (optionallymono-substituted by R^(q) as defined above), together a 4- to 5-memberedalkylidene radical to form a ring (optionally substituted with R^(q) asdefined above) or R^(g) is combined with R^(d) to form a diradicalselected from the group consisting of: --CH₂ CH₂ --, --CH₂ CH₂ CH₂ --and --CH═CH--;

R^(d) is --NH₂, --O⁻, C₁ -C₄ -alkyl (where the alkyl group is optionallymonosubstituted with R^(q) as defined above), or hydrogen, or R^(d) iscombined with R^(g) to form a diradical selected from the groupconsisting of: --CH₂ CH₂ --, --CH₂ CH₂ CH₂ -- and --CH═CH--;

provided that R^(d) is hydrogen only if at least one R^(a) or R^(c) isan amine group;

m is 0 or 1, if at least one R^(a) or R^(c) is an amine group;

m is 1 if neither R^(a) nor R^(c) is an amine group; and

M is selected from:

i) hydrogen;

ii) a pharmaceutically acceptable esterifying group or removablecarboxyl protecting group;

iii) an alkali metal or other pharmaceutically acceptable cation; or

iv) a negative charge.

DETAILED DESCRIPTION OF THE INVENTION

The manufacture of compounds of Formula I may be carried out in athree-stage synthesis scheme followed by a final step which allows forthe removal of any protecting groups. The objective of the firstsynthetic stage is to produce a base phenanthridine compound which maybe converted to the two-position substituent of the carbapenem ofFormula I. The objective of the second synthetic stage is to attach thebase phenanthridine to the carbapenem. Finally, the objective of thethird synthetic stage is to substitute the phenanthridine with thedesired R^(a). This third synthetic stage may be performed after thefirst synthetic stage or during or after the second synthetic stageaccording to the nature of the various R^(a).

Flow Sheets A-E demonstrate alternative first stage syntheses. FlowSheet F demonstrates a second stage synthesis. The third synthesisvaries according to the selected R^(a).

Referring to Flow Sheet A, 2-bromophenanthridine A1, obtained bybromination of phenanthridine, was modified to thetrimethylstannylphenanthridine A2. This is accomplished by reacting A1with hexamethylditin in the presence of a palladium (O) catalyst such astetrakis(triphenylphosphine)palladium and the like, and a phosphine,such as triphenylphosphine and the like, in a solvent such as toluene atan elevated temperature. The intermediate A2 may be incorporated in thesynthesis of the compounds of the instant invention or it may be furthermodified.

Thus, the trimethylstannyl phenanthridine A2 may be oxidized by reactingA2 with an oxidizing agent such as m-chloroperbenzoic acid (MCPBA),magnesium monoperoxyphthalate (MMPP) and the like, optionally in thepresence of a base such as sodium bicarbonate and the like.

Alternatively, the phenanthridinine A2 may be alkylated with a suitablealkylating agent, such as methyl triflate, ethyl triflate, and the like,in a suitable solvent, such as methylene chloride, tetrahydrofuran andthe like. This alkylated compound A4 may then be incorporated in thesynthesis of the compounds of the instant invention.

Also, the nitrogen atom of the phenanthridine A2 may be substituted withan amine group by reacting A2 with O-mesitylene sulfonylhydroxylamine(Y. Tamura, J. Minamikawa, M. Ikeda; Synthesis, 1977, 1-17) and thelike, to provide the phenanthridine A5.

The N-oxide A3 may be methylated to provide phenanthridine A6.Intermediate A6 may be reacted with a nucleophilic reagent, such assodium cyanide, potassium cyanide, sodium methoxide, ammonia,methylamine and the like to provide the phenanthridine A7 having asubstituent in the 6-position (R^(c) is --OCH₃, --NH₂, --NHCH₃,--N(CH₃)₂, --CN, and the like) (L. Stephenson and W. K. Warburton, J.Chem. Soc. (C), 1355(1970)). Such an intermediate A7 may then besubstituted on the ring nitrogen by a method described hereinabove.##STR7##

Alternatively, if the substitution pattern is not accessible from acommercially available phenanthridine, the substituted phenanthridinemay be constructed from monocyclic components. Referring to Flow SheetsB and C this alternative synthesis can be generally described as adirected ortho metallation reaction to prepare starting materialsrequired for a Suzuki cross-coupling reaction, ring closure to produce asuitably substituted phenanthridone and subsequent reductivedehalogenation to produce the desired phenanthridine platform. The firstpart of this suggested synthesis is utilized to produce similarphenanthridone and phenanthridine compounds by Snieckus, V., Chem. Rev.1990, 90, 879-933; Fu. J. M. and Snieckus, V., Tetrahedron Lett. 1990,31, p. 1665; Siddiqui, M. A., et al., Tetrahedron Lett., Vol. 29, No.43, 5463-5466 (1988); Mills, R. J., et al., J. Org. Chem., 1989, 54,4372-4385; Mills, R. J., J. Org. Chem., 1989, 54, 4386-4390; and Suzuki,A., et al., Synthetic Communications, 11(7), 513-519 (1981).

Referring to Flow Sheet B, compound B-1, which has as a substituent adirected metallation group (DMG), is utilized by methods according toSnieckus, et al., above. The function of the directed metallation group(DMG) is to orchestrate adornment of the aromatic ring. It is highlydesirable of the DMG that it also provide a precursor substituent forthe necessary carboxy function or amino function forming the amidelinkage of the object phenanthridone or the imine function of the objectphenanthridine. Suitable DMG to serve as a carboxyl precursor aresecondary and tertiary amides and oxazolino groups. Specifically, theseprecursors may be, for example, --CONEt₂, --CONHMe,4,4-dimethyl-2-oxazolinyl, and the like. In the instance of compoundB-1, DMG is of the carboxyl precursor type. Suitable DMG to serve as anamino precursor are protected primary and secondary amines.Specifically, these precursors may be --NH-tert-butoxycarbonyl(--NH-t-Boc), --NH-pivaloyl, phenylsulfonamido, and the like. CompoundC-1 as described below is by way of example, substituted by a DMG of theamino precursor type.

As the first step of Flow Sheet B, the bromine of compound B-1 isprotected through silylation via halogen metal exchange in the presenceof TMS chloride at between about -100° to -50° C. to produce aryl silaneB-2. Incorporation of an ortho substitutent R^(a) or its appropriateprecursor may be made on compound B-2 in accordance with standarddirected metallation procedures described by Snieckus, et al., above.The resultant substituted aryl silane B-3 is ortho metallated andtreated with an appropriate boron containing electrophile to obtain therequisite aryl boronic acid B-4. Suitable boron containing electrophilesinclude lower alkyl borates, such as trimethyl borate and tri-i-propylborate. Alternatively, and not shown in the Flow Sheets, the orthometallated compound may be treated with electrophiles such astrialkyltin halides providing the corresponding aryl stannanes which inturn are also useful intermediates in the production of biphenyls asreported by Stille, et al., J. Am. Chem. Soc., 1987, Vol. 109, page5478-5486. Preparation of biphenyl intermediate B-6 is accomplished inthe Flow Sheets utilizing the Suzuki cross-coupling procedure and theappropriately adorned aryl compounds B-4 and B-5. The Suzuki couplingcan be generally described as the reaction of an aryl boronic acid withan aryl halide or halide equivalent employingtetrakis(triphenylphosphine) palladium(O) catalyst in the presence of anaqueous solution of sodium carbonate in the solvents toluene/ethanol.The resulting biphenyl compound is isolated by standard methods.Compound B-5 may itself be produced by standard methods to obtain thehalogen substitution, X', the amino moiety --NR'₂ and the desiredsubstituents R^(a) or their precursors. The preferred halogen X' isbromine, iodine or the halogen equivalent trifluoromethanesulfonyloxy.The preferred amino moiety, --NR'₂, may be any of --NO₂, --N₃, protectedamine or amine. Biphenyl compound B-6 is subsequently transformed intothe halogenated biphenyl B-7 via ipso substitution of the trimethylsilylmoiety in methylene chloride or other appropriate solvent employingiodine monochloride. Any number of halogenating reagents are suitablesuch IBr, NBS, I₂, Br₂, etc., which must be compatible with the alreadyexisting functionalities. The halogenated phenanthridone B-8 is obtainedvia transamidation of the amino moiety with the latent carboxy precursorin the form of DMG. Alternatively, the phenanthridone may be formed viatransamidation of a biphenyl compound such as B-6 and the ipsosubstitution of the halogen performed upon the trimethylsilyl-phenanthridone.

The phenanthridone B-8 is subsequently transformed into thecorresponding trimethylstannyl phenanthridine B-10. Such atransformation may be accomplished by reacting the phenanthridone B-8with a halogenating agent such as phosphorous pentachloride, phosphorousoxychloride and the like to provide the halogenated phenanthridine B-9(where X" is the halogen). The halogenated phenanthridine B-9 may thenbe treated with hexamethylditin in the presence oftetrakis(triphenylphosphine)palladium (O) and triphenylphosphine toprovide the phenanthridine B-10. Phenanthridine B-10 is subsequentlytransformed as described hereinabove, and illustrated in Flow Sheet A,to provide the quaternized phenanthridine B-11 (where Q⁻ is thecounterion which is defined by the nature of the quaternizing agent).

Alternative syntheses of phenanthridones via a Beckmann Rearrangementare described by E. C. Horning et al. J. Am. Chem. Soc., 5153 (1952); H.L. Pan and T. L. Fletcher, J. Heterocyclic Chem., 7, 313 (1970); H. L.Pan and T. L. Fletcher, J. Heterocyclic Chem., 7, 597 (1970); H. L. Panand T. L. Fletcher, J. Med Chem., 12, 822 (1969); and A. Guy and J. P.Guette, Synthesis, 222 (1980). One Such synthetic route is illustratedin Examples 11 and 12. ##STR8##

Referring to Flow Sheet C, the regioisomeric phenanthridine C-5, andsubsequently the phenanthridine C-6, maybe produced in a manneranalogous to that of phenanthridone B-8. Compound C1 is dissimilar tocompound B-4 in that DMG of compound C1 is of the amino precursor type.Compound C1 is reacted with the appropriately adorned compound C2 toprepare biphenyl intermediate C3 utilizing the Suzuki cross-couplingprocedure. As above biphenyl compound C3 is transformed into halogenatedbiphenyl C4 via ipso substitution and subsequently dehydrated to providephenanthridine C5. Conversion of the phenanthridine C5 into thesubstituted phenanthridine C-6 may be accomplished by the methoddescribed herein above. ##STR9##

Referring to Flow Sheets D and E, the phenanthridine D-5 andphenanthridone E-5, having halogen group X in the 3-position (which willsubsequently lead to attachment of the carbapenem nucleus at a differentposition on the phenanthridine moiety) may be similarly produced fromstarting materials analogous to those employed in Flow Sheet B and C.

Specifically referring to Flow Sheet D, compound D-1, wherein DMGrepresents an amino precursor and X' is a suitable leading group, may bederived from readily available compounds, such as5-bromo-2-hydroxyaniline and the like. Compound D-1 is reacted with asuitably substituted phenyl boronic acid D-2 via a Suzuki cross-couplingprocedure to form the biphenyl compound D-3. The silyl moiety oncompound D-3 is then replaced with a suitable halogen, such as bromineor iodine via ipso substitution. The halogenated biphenyl D-4 then iscyclized to form the desired phenanthridine D-5. This phenanthridine maybe subsequently converted to the trimethylstannyl phenanthridine by themethods described herein above. ##STR10##

Specifically referring to Flow Sheet E, the starting material, compoundE-1, may be derived from commercially available compounds, such as5-bromo salicyclic acid and the like. Compound E-1 is reacted with thesuitably substituted phenyl boronic acid E-2 via a Suzuki cross-couplingprocedure to form the biphenyl compound E-3. The silyl moiety onCompound E-3 is transformed into a halogen moiety via ipso substitution.The halogenated biphenyl E-4 is then cyclized to form the phenanthridoneE5 via transamidization. The phenanthridone intermediate may then beconverted to the phenanthridine as previously described. ##STR11##

The object compounds of Flow Sheets A-E, the various regioisomericphenanthridines, form the nucleus of the 2-position substitution of thecarbapenem compounds taught herein. As such they are shown to be R^(a)substituted. However, it is immediately clear to those skilled in theart that certain R^(a) listed above, if substituted on B-3, B-5, or both(or the corresponding intermediates found in Flow Sheets A and C-E)would not survive or permit the synthesis to the phenanthridines. Thus,where a certain R^(a) is desired, for example, on compound B-10 and thisR^(a) is not compatible with the synthesis scheme to produce B-10, thena compatible precursor substituent may be employed through thesynthesis.

The identity of the precursor substituent employed is not crucial solong as it does not interfere with the synthesis to the phenanthridineand so long as it may be thereafter converted to more desireablesubstitution. Preferred precursor substituents are methyl, hydroxymethyland protected hydroxymethyl.

Thus, for example as to the R^(a) substituent on compound B-10, it maybe an R^(a) with or without protecting groups stable to the conditionsof producing compound B-10 and stable to the conditions of subsequentlyadding B-10 to the carbapenem. Alternatively, it may be a stableprecursor substituent which is stable to the conditions of making B-10,which is optionally stable to the conditions of adding B-10 to thecarbapenem and which is convertible to a desired R^(a) or to anotherprecursor substituent.

As stated above, the second stage synthesis is to attach the basephenanthridine to the 2-position of the carbapenem.

Flow Sheet F shows a second stage synthesis, i.e. attachment of the basephenanthridine, such as B-11, to the 2-position of the carbapenem. Thissynthesis involves a palladium catalyzed cross-coupling reaction betweena carbapenem triflate and a suitably substituted arylstannane, a processwhich is described in U.S. patent application No. 485,096 filed Feb. 26,1990. Referring to Flow Sheet F, the 2-oxocarbapenam F-1 is reacted witha suitable trifluoromethanesulfonyl source, such astrifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chlorideand the like, in the presence of an organic nitrogen base, such astriethylamine, diisopropylamine and the like, in polar aprotic solvent,such as tetrahydrofuran or methylene chloride. The hydroxyl moiety maythen be protected. Thus, optionally an organic nitrogen base, such astriethylamine and the like, is added to the reaction solution followedimmediately by a silylating agent, such as trimethylsilyltrifluoromethanesulfonate or triethylsilyl triflate to provideintermediate F2 where R^(p) is an alkyl silyl group. Regardless ofwhether the hydroxyl moiety is left unprotected or is modified with aprotecting group, an aprotic polar coordinating solvent, such as DMF,1-methyl-2-pyrrolidinone and the like, is then added. This is followedby the addition of a palladium compound, such astris(dibenzylideneacetone)dipalladium chloroform, palladium acetate andthe like, the stannane B-11 and optionally a suitably substitutedphenylphosphine, such as tris(4-methoxyphenyl)phosphine,tris(2,4,6-trimethoxyphenyl)phosphine and the like. A halide source,such as lithium chloride, zinc chloride, tetrabutylammonium chloride,diisopropylamine hydrochloride, triethylamine hydrochloride and thelike, is added and the reaction solution is allowed to warm and isstirred at a suitable temperature, such as 0° to 50° C. for from a fewminutes to 7 days. The carbapenem F-3 is obtained by conventionalisolation/purification methodology known in the art.

Generally speaking, the mild conditions of the synthesis shown in FlowSheet F allow for a wide range of functional groups R^(a) to be present.However, in certain cases it is advantageous for the R^(a)substituent(s) of the stannane B-11 to be introduced in a protected orprecursory form. Final elaboration of R^(a) from a precursorsubstituent, e.g. hydroxymethyl, may be accomplished on carbapenemintermediate F-3. Removal of hydroxyl and carboxyl protecting groupsthen provides the final compound of Formula I. Such final elaborationand deprotection is described in further detail below. ##STR12##

The steps for preparing the 2-oxocarbapenam intermediate F-1 are wellknown in the art and are explained in ample detail by D. G. Melillo etal., Tetrahedron Letters, 21, 2783 (1980), T. Salzmann et al., J. Am.Chem. Soc., 102, 6161 (1980), and L. M. Fuentes, I. Shinkai, and T. N.Salzmann, J. Am. Chem. Soc., 108, 4675 (1986). The syntheses are alsodisclosed in U.S. Pat. Nos. 4,269,772, 4,350,631, 4,383,946 and4,414,155 all assigned to Merck and Company, Inc.

The general synthesis description depicted above in the Flow SheetsR^(a) shows a protected 1-hydroxyethyl substitution on the 6-position ofthe carbapenem. After final deprotection, a 1-hydroxyethyl substituentis obtained, which is preferred in most cases. However, it has beenfound that with certain 2-position-side-chain selections, the ultimatebalance of favorable properties in the overall molecule may be enhancedby selection of the 6-(1-fluoroethyl) moiety instead. Preparation of6-fluoroalkyl compounds within the scope of the present invention iscarried out in a straightforward manner using techniques well known inthe art of preparing carbapenem antibacterial compounds. See, e.g., J.G. deVries et al., Heterocycles, 23 (8), 1915 (1985); BE 900 718 A(Sandoz) and Japanese Patent Pub. No. 6-0163-882-A (Sanruku Ocean).

In preferred compounds of Formula I, R¹ is hydrogen. More preferably, R¹is hydrogen and R² is (R)--CH₃ CH(OH)-- or (R)--CH₃ CH(F)--. In the mostpreferred case, R¹ is hydrogen and R² is (R)--CH₃ CH(OH)--. While R═H isusually preferred, there are instances in which R═CH₃ may provideimproved chemical stability, water solubility, or pharmacokineticbehavior. The substituent R═CH₃ may be of either configuration, i.e.,the α or β-stereoisomer. Additionally, in preferred compounds, at leastone R^(a) in the 4-, 7- or 8-position of the phenanthridine or R^(c) isother than hydrogen if Y is substituent b), at least one R^(a) in the3-, 4- or 7-position of the phenanthridine or R^(c) is other thanhydrogen if Y is substituent a), at least one R^(a) in the 1-, 7- or8-position of the phenanthridine or R^(c) is other than hydrogen if Y issubstituent d), or at least one R^(a) in the 3-, 4- or 10-position ofthe phenanthridine or R^(c) is other than hydrogen if Y is substituentc). In the most preferred compounds, in total, up to two R.sup. asubstituents in two of those positions are other than hydrogen.

The formulas depicting substituent Y show positively charged states forthat substituent. It is understood that certain embodiments ofsubstituent Y, which are cationic by virtue of having a protonatinghydrogen atom attached to the nitrogen, may also exist or be producedunder certain conditions as a neutral substituent by virtue of theabsence of such a hydrogen atom. Whether such a substituent Y will bepredominately cationic or neutral in a given physical state will begoverned by principles of acid-base chemistry, which are well known tothose skilled in the art. For example, the particular ratio of neutralform to cationic form will depend upon the basicity of thephenanthridinyl nitrogen and the acidity of the solution. When thephenanthridinyl substituent is in a protonated quaternized state, thecompound exists as a zwitterion which is internally balanced as tocharge. When the phenanthridinyl substituent is not in a protonatedquaternized state, the compound exists as a anionic carboxylic acidsalt, balance with an appropriate cation, M.

Suitable R^(a) are described above in the text associated with FormulaI. Among preferred R^(a) are C₁₋₄ alkyl mono-substituted with hydroxy,such as, hydroxymethyl; formyl; alkoxycarbonyl, such as, --COOMe;carbamoyl, such as, --CONH₂ ; hydroxoximinomethyl, such as, --CH═NOH orcyano.

For example, when Y is substituent b), in regard to this preferredsubstitution, the hydroxymethyl groups may be obtained in the 4, 7, and8-positions of the phenanthridine as follows. Thus referring to FlowSheet B, methyl, as a precursor substituent, is substituted on startingmaterials B-3 and/or B-5 in the appropriate positions by well knowmeans. Subsequently the methyl substituent of methyl-substituted B-3,B-5, B-6 or B-8 may be oxidized e.g. to carboxy with ruthenium tetroxideor to bromomethyl with N-bromosuccinimide. The resultant carboxy orbromomethyl substituted starting material may be further elaborated. Inthe case of the bromomethyl substituent, conversion to a hydroxymethylsubstituted precursor may be accomplished by a three-step sequence.Reaction of the bromomethyl compound with potassium acetate in DMF at60°-100° C. gives the corresponding acetoxymethyl compound. Removal ofthe acetate group, e.g. by hydrolysis with methanolic sodium hydroxideor by reduction with diisobutylaluminium hydride in THF, gives thehydroxymethyl substituted compound which may then be incorporated in thesynthesis of a correspondingly substituted B11. When necessary thehydroxymethyl moiety may be protected by silylation witht-butyldimethylsilyl chloride, triethylamine and 4-dimethylaminopyridinein dichloromethane or t-butyldimethylsilyl chloride and imidazole inDMF. Further elaboration of B-3, B-5, B-6, B-8 or B-10 provides othermoieties as described hereinbelow.

The preferred formyl substitution on the phenanthridine may be obtainedfrom the hydroxymethyl substituted starting material just described by aSwern oxidation. For example, the hydroxymethyl is oxidized in methylenechloride at from -70° C. to room temperature employing oxalylchloride-dimethyl sulfoxide followed by triethylamine as the activeagent. Obviously, the position of the resultant formyl substitution willdepend upon the position of the hydroxymethyl substitution on compoundB-3, B-5 B-6, B-8 or B-10.

The preferred --CH═NOH substitution on the phenanthridine may beconveniently obtained from the formyl substitution just described. Thisis accomplished simply by exposing the formyl substituted compound tohydroxylamine in an appropriate solvent at room temperature.

The preferred cyano substitution on the phenanthridine may be obtainedfrom the --CH═NOH substitution just described. The --CH═NOH substitutedcompound is dehydrated with triflic anhydride and triethylamine in asolvent at -70° C.

The preferred alkoxycarbonyl substitution on the phenanthridine may beobtained from the hydroxymethyl substituted starting material. Forexample, the substituted compound B-7 or B-8 is oxidized with Jonesreagent to convert the hydroxymethyl substituent to a carboxylic acidgroup. This carboxylic acid group may then be esterified by procedureswell known in the art, such as treatment with diazomethane and the like.

The preferred carbamoyl substitution on the phenanthridine, may beobtained by oxidizing the hydroxymethyl group with Jones reagent to thecorresponding carboxylic acid group as described above. This carboxylicacid substituent is converted to the carboxamide group, --CONH₂, bysequentially contacting with1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,1-hydroxybenzotriazole, and ammonia in an organic solvent at roomtemperature. Substituted amides may of course be obtained by replacingammonia with the corresponding substituted amine.

In the preparation methods described above, the carboxyl group at the3-position and the hydroxyl group at the 8-position of the carbapenemremain blocked by protecting groups until the penultimate product isprepared. Deblocking may be carried out in a conventional manner. Forcompounds prepared via Flow Sheet F, if the hydroxyethyl moiety has beenprotected deprotection is conducted sequentially. Thus, compound F-3where R^(p) is a trialkylsilyl is exposed initially to aqueous acidicconditions, acetic acid or dilute HCl or the like, in an organic solventsuch as tetrahydrofuran at 0° C. to ambient temperature for from a fewminutes to several hours. The desilylated carbapenem may be isolated byconventional techniques, but is more conveniently taken into the finaldeprotection process. Thus, addition of a base such as NaHCO₃ or KHCO₃,and optionally a buffer such as MOPS buffer, phosphate buffer and thelike, and a suitable catalyst, such as 5%-10% Pd/C, 5%-10% Rh/Al₂ O₃,5%-10% Rh/C and the like, followed by hydrogenation provides for theremoval of the p-nitrobenzyl protecting group and the formation of thefinal compound of Formula I.

With reference to the above definitions, "alkyl" means a straight orbranched chain aliphatic hydrocarbon radical.

The term "heteroatom" means N, S, or O, selected on an independentbasis.

The term "heteroaryl" has been defined herein, in relation to the R^(x)group, to have a specific and limited meaning, being only monocyclic. Itis required that the monocyclic heteroaryl have at least one nitrogenatom, and optionally at most only one additional oxygen or sulfurheteroatom may be present. Heteroaryls of this type are pyrrole andpyridine (1N); and oxazole, thiazole or oxazine (1N+1 O or 1 S). Whileadditional nitrogen atoms may be present together with the firstnitrogen and oxygen or sulfur, giving, e.g., a thiadiazole (2N's+1S),the preferred heteroaryls are those where only nitrogen heteroatoms arepresent when there is more than one. Typical of these are pyrazole,imidazole, pyrimidine and pyrazine (2 N's) and triazine (3 N's).

The heteroaryl group of R^(x) is always optionally mono-substituted byR^(q), defined above, and substitution can be on one of the carbon atomsor one of the heteroatoms, although in the latter case certainsubstitutent choices may not be appropriate.

The ring system formed when R^(g) is combined with R^(d) to form adiradical which forms a ring is easily understood by those of ordinaryskill in the art and may be illustrated by the following structures:##STR13## Preparation of the such a ring system has been previouslydescribed in the literature (R. F. Cookson and R. E. Rodway, J. Chem.Soc. Perkin I, 1850 (1975)).

The compounds of the instant invention are characterized by substitutionon the ring nitrogen of the phenanthridinyl moiety which creates apositive charge at that nitrogen. Another term for such a charge is thatthe nitrogen is quaternized. This charge is offset by the carboxylatemoiety in the 3-position of the carbapenem, thus giving the molecule anoverall neutral characteristic. Usually such a nitrogen substitution ischaracterized by a covalent bond which is unaffected by the pH of thesolution in which the compound is dissolved. However, when the ringsubstituent R^(a) or R^(c) is an amine group in conjugation with thering nitrogen, said ring nitrogen may be sufficiently basic in charactersuch that at physiological pH said ring nitrogen may be protonated andthus positively charged. This charge is offset by the carboxylate moietyin the 3-position of the carbapenem. The structure below illustratesthis situation where the R^(c) substitution is an amine and the ringnitrogen is substituted by a hydrogen atom. It is understood that thisinvention encompasses such a pH dependent charged substitution on thering nitrogen. ##STR14##

Also understood by the instant invention is a compound wherein thephenanthridine moiety is substituted by an amine group but the ringnitrogen is not sufficiently basic in character to be protonated atphysiological pH. This latter embodiment of the instant invention has aphenanthridine moiety which has no substituent on the ring nitrogen andthe negative charge of the carboxylate moiety in the 3-position of thecarbapenem is offset by an alkali metal or other pharmaceuticallyacceptable cation.

Listed in Tables I, II, III and IV are specific compounds of the instantinvention. It is understood that when R^(d) is O⁻ or is absent, a cationM must also be associated with the compound described so as to renderthe compound neutral overall. These compounds are meant to beillustrative and are not limiting.

                                      TABLE I                                     __________________________________________________________________________     ##STR15##                                                                                    R.sup.a'                                                      R  R.sup.a'     Position                                                                           T  R.sup.c   R.sup.d                                     __________________________________________________________________________    H  CN           4    OH H         CH.sub.3                                    H  CONH.sub.2   4    OH H         CH.sub.3                                    H  CONMe.sub.2  4    OH H         CH.sub.3                                    H  CHO          4    OH H         CH.sub.3                                    H  SCH.sub.3    4    OH H         CH.sub.3                                    H  SOCH.sub.3   4    OH H         CH.sub.3                                    H   SO.sub.2 CH.sub.3                                                                         4    OH H         CH.sub.3                                    H  F            4    OH H         CH.sub.3                                    H  SO.sub.2 NH.sub.2                                                                          4    OH H         CH.sub.3                                    H  CH.sub.2 OH  8    OH H         CH.sub.3                                    H  CN           8    OH H         CH.sub.3                                    H  CONH.sub.2   8    OH H         CH.sub.3                                    H  CHO          8    OH H         CH.sub.3                                    H  CH.sub.2 OH  7    OH H         CH.sub.3                                    H  CN           7    OH H         CH.sub.3                                    H  CONH.sub.2   7    OH H         CH.sub.3                                    H  CHO          7    OH H         CH.sub.3                                    H  CN           4    F  H         CH.sub.3                                    H  CHO          4    F  H         CH.sub.3                                    H  CONH.sub.2   4    F  H         CH.sub.3                                    CH.sub.3                                                                         CN           4    OH H         CH.sub.3                                    CH.sub.3                                                                         CONH.sub.2   4    OH H         CH.sub.3                                    CH.sub.3                                                                         CHO          4    OH H         CH.sub.3                                    CH.sub.3                                                                         CN           4    F  H         CH.sub.3                                    H  CN           4    OH H         Et                                          H  CONH.sub.2   4    OH H         Pr                                          H  CONH.sub.2   4    OH H         Bu                                          H  CF.sub.3     8    OH H         CH.sub.3                                    H  OCH.sub.3    9    OH H         CH.sub. 3                                   H  OCH.sub.2 CO.sub.2 CH.sub.3                                                                10   OH H         CH.sub.3                                    H  Cl           4,7,8                                                                              OH H         CH.sub.3                                    H  OH           9    OH H         CH.sub.3                                    H  OCOCH.sub.3  8    OH H         CH.sub.3                                    H  OCONH.sub.2  8    OH H         CH.sub.3                                    H  SCH.sub.2 CH.sub.2 OH                                                                      8    OH H         CH.sub.3                                    H  SOCH.sub.2 CH.sub.2 OH                                                                     9    OH H         CH.sub.3                                    H  SCH.sub.2 CONH.sub.2                                                                       4    OH H         CH.sub.3                                    H  SO.sub.2 NMe.sub.2                                                                         4,8  OH H         CH.sub.3                                    H  NHCHO        8    OH H         CH.sub.3                                    H  --                OH NHCH.sub.2 CONH.sub.2                                                                   CH.sub.3                                    H  --                OH N(CH.sub.3).sub.2                                                                       CH.sub.3                                    H  --                F  N(CH.sub.3).sub.2                                                                       CH.sub.3                                    CH.sub.3                                                                         --                OH N(CH.sub.3).sub.2                                                                       CH.sub.3                                    H  CH.sub.2 OH  8    OH H         O.sup.-                                     H  CH.sub.2 OH  8    OH H         NH.sub.2                                    H  CH.sub.2 OH  8    OH H         CH.sub.2 CH.sub.2 OH                        H  CH.sub.2 OH  8    OH H         CH.sub.2 CH.sub.2 CH.sub.2 CN               H  NHCOCH.sub.3 9    OH H         CH.sub.3                                    H  NHCOCH.sub.3 10   OH H         CH.sub.3                                    H  NHSO.sub.2 CH.sub.3                                                                        4    OH H         CH.sub.3                                    H  COMe         4    OH H         CH.sub.3                                    H  COCH.sub.2 OH                                                                              7    OH H         CH.sub.3                                    H  CHNOH        8    OH H         CH.sub.3                                    H  CHNOMe       7    OH H         CH.sub.3                                    H  CHNOCH.sub.2 CO.sub.2 Me                                                                   8    OH H         CH.sub.3                                    H  CHNOCM.sub.e2 CO.sub.2 Me                                                                  8    OH H         CH.sub.3                                    H  CHNOCMe.sub.2 CONH.sub.2                                                                   9    OH H         CH.sub.3                                    H  CO.sub.2 CH.sub.2 CH.sub.2 OH                                                              10   OH H         CH.sub.3                                    H  CONHCH.sub.3 4    OH H         CH.sub.3                                    H  CONHCH.sub.2 CN                                                                            4    OH H         CH.sub.3                                    H  CONHCH.sub.2 CN                                                                            4    F  H         CH.sub.3                                    CH.sub.3                                                                         CONHCH.sub.2 CN                                                                            4    OH H         CH.sub.3                                    H  CONHCH.sub.2 CONH.sub.2                                                                    8    OH H         CH.sub.3                                    H  CONHCH.sub.2 CO.sub.2 CH.sub.3                                                             9    OH H         CH.sub.3                                    H  CONHOH       4    OH H         CH.sub.3                                    H  CONHOCH.sub.3                                                                              10   OH H         CH.sub.3                                    H   CO.sub.2 CH.sub.3                                                                         4    OH H         CH.sub.3                                    tetrazolyl                                                                       8            OH   H  CH.sub.3                                              H  SCF.sub.3    4    OH H         CH.sub.3                                    H  PO.sub.2 NH.sub.2                                                                          4    OH H         CH.sub.3                                    H  CONHSO.sub.2 Ph                                                                            4    OH H         CH.sub.3                                    H  CONHSO.sub.2 NH.sub.2                                                                      4    OH H         CH.sub.3                                    H  SO.sub.2 CF.sub.3                                                                          8    OH H         CH.sub.3                                    H  SO.sub.2 NHCN                                                                              4    OH H         CH.sub.3                                    H  SO.sub.2 NHCONH.sub.2                                                                      4    OH H         CH.sub.3                                    H  CHCHCN       4    OH H         CH.sub.3                                    H  CHCHCONH.sub.2                                                                             4    OH H         CH.sub.3                                    H  CCCN         4    OH H         CH.sub.3                                    H  CH.sub.2 N.sub.3                                                                           7    OH H         CH.sub.3                                    H  CH.sub.2 CO.sub.2 Me                                                                       10   OH H         CH.sub.3                                    H  SO.sub.2 CH.sub.2 CH.sub.2 OH                                                              4    OH H         CH.sub.3                                    H  CH.sub.2 I   8    OH H         CH.sub.3                                    H  I            4    OH H         CH.sub.3                                    H  Br           4    OH H         CH.sub.3                                    H  --                OH H         CH.sub.2 CH.sub.2 CH.sub.3                  H  --                OH OCH.sub.3 CH.sub.3                                    H  --                OH NHCH.sub.2 CH.sub.2 OH                                                                  CH.sub.3                                    H  --                OH N-pyrrol- CH.sub.3                                                            idinyl                                                H  --                OH NH.sub.2  H                                           __________________________________________________________________________

                                      TABLE II                                    __________________________________________________________________________     ##STR16##                                                                                    R.sup.a'                                                      R  R.sup.a'     Position                                                                           T  R.sup.c   R.sup.d                                     __________________________________________________________________________    H  CN           7    OH H         CH.sub.3                                    H  CONH.sub.2   7    OH H         CH.sub.3                                    H  CONMe.sub.2  7    OH H         CH.sub.3                                    H  CHO          7    OH H         CH.sub.3                                    H  SCH.sub.3    7    OH H         CH.sub.3                                    H  SOCH.sub.3   7    OH H         CH.sub.3                                    H  SO.sub.2 CH.sub.3                                                                          7    OH H         CH.sub.3                                    H  F            7    OH H         CH.sub.3                                    H  SO.sub.2 NH.sub.2                                                                          7    OH H         CH.sub.3                                    H  CH.sub.2 OH  3    OH H         CH.sub.3                                    H  CN           3    OH H         CH.sub.3                                    H  CONH.sub.2   3    OH H         CH.sub.3                                    H  CHO          3    OH H         CH.sub.3                                    H  CH.sub.2 OH  4    OH H         CH.sub.3                                    H  CN           4    OH H         CH.sub.3                                    H  CONH.sub.2   4    OH H         CH.sub.3                                    H  CHO          4    OH H         CH.sub.3                                    H  CN           7    F  H         CH.sub.3                                    H  CHO          7    F  H         CH.sub.3                                    H  CONH.sub.2   7    F  H         CH.sub.3                                    CH.sub.3                                                                         CN           7    OH H         CH.sub.3                                    CH.sub.3                                                                         CONH.sub.2   7    OH H         CH.sub.3                                    CH.sub.3                                                                         CHO          7    OH H         CH.sub.3                                    CH.sub.3                                                                         CN           7    F  H         CH.sub.3                                    H  CN           7    OH H         Et                                          H  CONH.sub.2   7    OH H         Pr                                          H  CONH.sub.2   7    OH H         Bu                                          H  CF.sub.3     3    OH H         CH.sub.3                                    H  OCH.sub.3    2    OH H         CH.sub.3                                    H  OCH.sub.2 CO.sub.2 CH.sub.3                                                                1    OH H         CH.sub.3                                    H  Cl           3,4,7                                                                              OH H         CH.sub.3                                    H  OH           2    OH H         CH.sub.3                                    H  OCOCH.sub.3  3    OH H         CH.sub.3                                    H  OCONH.sub.2  3    OH H         CH.sub.3                                    H  SCH.sub.2 CH.sub.2 OH                                                                      3    OH H         CH.sub.3                                    H  SOCH.sub.2 CH.sub.2 OH                                                                     2    OH H         CH.sub.3                                    H  SCH.sub.2 CONH.sub.2                                                                       7    OH H         CH.sub.3                                    H  SO.sub.2 NMe.sub.2                                                                         7,3  OH H         CH.sub.3                                    H  NHCHO        3    OH H         CH.sub.3                                    H  --                OH NHCH.sub.2 CONH.sub.2                                                                   CH.sub.3                                    H  --                OH N(CH.sub.3).sub.2                                                                       CH.sub.3                                    H  --                F  N(CH.sub.3).sub.2                                                                       CH.sub.3                                    CH.sub.3                                                                         --                OH N(CH.sub.3).sub.2                                                                       CH.sub.3                                    H  CH.sub.2 OH  3    OH H         O.sup.-                                     H  CH.sub.2 OH  3    OH H         NH.sub.2                                    H  CH.sub.2 OH  3    OH H         CH.sub.2 CH.sub.2 OH                        H  CH.sub.2 OH  3    OH H         CH.sub.2 CH.sub. 2 CH.sub.2 CN              H  NHCOCH.sub.3 2    OH H         CH.sub.3                                    H  NHCOCH.sub.3 1    OH H         CH.sub.3                                    H  NHSO.sub.2 CH.sub.3                                                                        7    OH H         CH.sub.3                                    H  COMe         7    OH H         CH.sub.3                                    H  COCH.sub.2 OH                                                                              4    OH H         CH.sub.3                                    H  CHNOH        3    OH H         CH.sub.3                                    H  CHNOMe       4    OH H         CH.sub.3                                    H  CHNOCH.sub.2 CO.sub.2 Me                                                                   3    OH H         CH.sub.3                                    H  CHNOCM.sub.e2 CO.sub.2 Me                                                                  3    OH H         CH.sub.3                                    H  CHNOCMe.sub.2 CONH.sub.2                                                                   2    OH H         CH.sub.3                                    H  CO.sub.2 CH.sub.2 CH.sub.2 OH                                                              1    OH H         CH.sub.3                                    H  CONHCH.sub.3 7    OH H         CH.sub.3                                    H  CONHCH.sub.2 CN                                                                            7    OH H         CH.sub.3                                    H  CONHCH.sub.2 CN                                                                            7    F  H         CH.sub.3                                    CH.sub.3                                                                         CONHCH.sub.2 CN                                                                            7    OH H         CH.sub.3                                    H  CONHCH.sub.2 CONH.sub.2                                                                    3    OH H         CH.sub.3                                    H  CONHCH.sub.2 CO.sub.2 CH.sub.3                                                             2    OH H         CH.sub.3                                    H  CONHOH       7    OH H         CH.sub.3                                    H  CONHOCH.sub.3                                                                              1    OH H         CH.sub.3                                    H  CO.sub.2 CH.sub.3                                                                          7    OH H         CH.sub.3                                    tetrazolyl                                                                       3            OH   H  CH.sub.3                                              H  SCF.sub.3    7    OH H         CH.sub.3                                    H  PO.sub.2 NH.sub.2                                                                          7    OH H         CH.sub.3                                    H  CONHSO.sub.2 Ph                                                                            7    OH H         CH.sub.3                                    H  CONHSO.sub.2 NH.sub.2                                                                      7    OH H         CH.sub.3                                    H  SO.sub.2 CF.sub.3                                                                          3    OH H         CH.sub.3                                    H  SO.sub.2 NHCN                                                                              7    OH H         CH.sub.3                                    H  SO.sub.2 NHCONH.sub.2                                                                      7    OH H         CH.sub.3                                    H  CHCHCN       7    OH H         CH.sub.3                                    H  CHCHCONH.sub.2                                                                             7    OH H         CH.sub.3                                    H  CCCN         7    OH H         CH.sub.3                                    H  CH.sub.2 N.sub.3                                                                           4    OH H         CH.sub.3                                    H  CH.sub.2 CO.sub.2 Me                                                                       1    OH H         CH.sub.3                                    H  SO.sub.2 CH.sub.2 CH.sub.2 OH                                                              7    OH H         CH.sub.3                                    H  CH.sub.2 I   3    OH H         CH.sub.3                                    H  I            7    OH H         CH.sub.3                                    H  Br           7    OH H         CH.sub.3                                    H  --                OH H         CH.sub.2 CH.sub.2 CH.sub.3                  H  --                OH OCH.sub.3 CH.sub.3                                    H  --                OH NHCH.sub.2 CH.sub.2 OH                                                                  CH.sub.3                                    H  --                OH N-pyrrol- CH.sub.3                                                            idinyl                                                H  --                OH NH.sub.2  H                                           __________________________________________________________________________

                                      TABLE III                                   __________________________________________________________________________     ##STR17##                                                                                    R.sup.a'                                                      R  R.sup.a'     Position                                                                           T  R.sup.c   R.sup.d                                     __________________________________________________________________________    H  CN           1    OH H         CH.sub.3                                    H  CONH.sub.2   1    OH H         CH.sub.3                                    H  CONMe.sub.2  1    OH H         CH.sub.3                                    H  CHO          1    OH H         CH.sub.3                                    H  SCH.sub.3    1    OH H         CH.sub.3                                    H  SOCH.sub.3   1    OH H         CH.sub.3                                    H  SO.sub.2 CH.sub. 3                                                                         1    OH H         CH.sub.3                                    H  F            1    OH H         CH.sub.3                                    H  SO.sub.2 NH.sub.2                                                                          1    OH H         CH.sub.3                                    H  CH.sub.2 OH  8    OH H         CH.sub.3                                    H  CN           8    OH H         CH.sub.3                                    H  CONH.sub.2   8    OH H         CH.sub.3                                    H  CHO          8    OH H         CH.sub.3                                    H  CH.sub.2 OH  7    OH H         CH.sub.3                                    H  CN           7    OH H         CH.sub.3                                    H  CONH.sub.2   7    OH H         CH.sub.3                                    H  CHO          7    OH H         CH.sub.3                                    H  CN           1    F  H         CH.sub.3                                    H  CHO          1    F  H         CH.sub.3                                    H  CONH.sub.2   1    F  H         CH.sub.3                                    CH.sub.3                                                                         CN           1    OH H         CH.sub.3                                    CH.sub.3                                                                         CONH.sub.2   1    OH H         CH.sub.3                                    CH.sub.3                                                                         CHO          1    OH H         CH.sub.3                                    CH.sub.3                                                                         CN           1    F  H         CH.sub.3                                    H  CN           1    OH H         Et                                          H  CONH.sub.2   1    OH H         Pr                                          H  CONH.sub.2   1    OH H         Bu                                          H  CF.sub.3     8    OH H         CH.sub.3                                    H  OCH.sub.3    9    OH H         CH.sub.3                                    H   OCH.sub.2 CO.sub.2 CH.sub.3                                                               10   OH H         CH.sub.3                                    H  Cl           1,7,8                                                                              OH H         CH.sub.3                                    H  OH           9    OH H         CH.sub.3                                    H  OCOCH.sub.3  8    OH H         CH.sub.3                                    H  OCONH.sub.2  8    OH H         CH.sub.3                                    H  SCH.sub.2 CH.sub.2 OH                                                                      8    OH H         CH.sub.3                                    H  SOCH.sub.2 CH.sub.2 OH                                                                     9    OH H         CH.sub.3                                    H  SCH.sub.2 CONH.sub.2                                                                       1    OH H         CH.sub.3                                    H  SO.sub.2 NMe.sub.2                                                                         1,8  OH H         CH.sub.3                                    H  NHCHO        8    OH H         CH.sub.3                                    H  --                OH NHCH.sub.2 CONH.sub.2                                                                   CH.sub.3                                    H  --                OH N(CH.sub.3).sub.2                                                                       CH.sub.3                                    H  --                F  N(CH.sub.3).sub.2                                                                       CH.sub.3                                    CH.sub.3                                                                         --                OH N(CH.sub.3).sub.2                                                                       CH.sub.3                                    H  CH.sub.2 OH  8    OH H         O.sup.-                                     H  CH.sub.2 OH  8    OH H         NH.sub.2                                    H  CH.sub.2 OH  8    OH H         CH.sub.2 CH.sub.2 OH                        H  CH.sub.2 OH  8    OH H         CH.sub.2 CH.sub.2 CH.sub.2 CN               H  NHCOCH.sub. 3                                                                              9    OH H         CH.sub.3                                    H  NHCOCH.sub.3 10   OH H         CH.sub.3                                    H  NHSO.sub.2 CH.sub.3                                                                        1    OH H         CH.sub.3                                    H  COMe         1    OH H         CH.sub.3                                    H  COCH.sub.2 OH                                                                              7    OH H         CH.sub.3                                    H  CHNOH        8    OH H         CH.sub.3                                    H  CHNOMe       7    OH H         CH.sub.3                                    H  CHNOCH.sub.2 CO.sub.2 Me                                                                   8    OH H         CH.sub.3                                    H  CHNOCM.sub.e2 CO.sub.2 Me                                                                  8    OH H         CH.sub.3                                    H  CHNOCMe.sub.2 CONH.sub.2                                                                   9    OH H         CH.sub.3                                    H  CO.sub.2 CH.sub.2 CH.sub.2 OH                                                              10   OH H         CH.sub.3                                    H  CONHCH.sub.3 1    OH H         CH.sub.3                                    H  CONHCH.sub.2 CN                                                                            1    OH H         CH.sub.3                                    H  CONHCH.sub.2 CN                                                                            1    F  H         CH.sub.3                                    CH.sub.3                                                                         CONHCH.sub.2 CN                                                                            1    OH H         CH.sub.3                                    H  CONHCH.sub.2 CONH.sub.2                                                                    8    OH H         CH.sub.3                                    H  CONHCH.sub.2 CO.sub.2 CH.sub.3                                                             9    OH H         CH.sub.3                                    H  CONHOH       1    OH H         CH.sub.3                                    H  CONHOCH.sub.3                                                                              10   OH H         CH.sub.3                                    H  CO.sub.2 CH.sub. 3                                                                         1    OH H         CH.sub.3                                    tetrazolyl                                                                       8            OH   H  CH.sub.3                                              H  SCF.sub.3    1    OH H         CH.sub.3                                    H  PO.sub.2 NH.sub.2                                                                          1    OH H         CH.sub.3                                    H  CONHSO.sub.2 Ph                                                                            1    OH H         CH.sub.3                                    H  CONHSO.sub.2 NH.sub.2                                                                      1    OH H         CH.sub.3                                    H  SO.sub.2 CF.sub.3                                                                          8    OH H         CH.sub.3                                    H  SO.sub.2 NHCN                                                                              1    OH H         CH.sub.3                                    H  SO.sub.2 NHCONH.sub.2                                                                      1    OH H         CH.sub.3                                    H  CHCHCN       1    OH H         CH.sub.3                                    H  CHCHCONH.sub.2                                                                             1    OH H         CH.sub.3                                    H  CCCN         1    OH H         CH.sub.3                                    H  CH.sub.2 N.sub.3                                                                           7    OH H         CH.sub.3                                    H  CH.sub.2 CO.sub.2 Me                                                                       10   OH H         CH.sub.3                                    H  SO.sub.2 CH.sub.2 CH.sub.2 OH                                                              1    OH H         CH.sub.3                                    H  CH.sub.2 I   8    OH H         CH.sub.3                                    H  I            1    OH H         CH.sub.3                                    H  Br           1    OH H         CH.sub.3                                    H  --                OH H         CH.sub.2 CH.sub.2 CH.sub.3                  H  --                OH OCH.sub.3 CH.sub.3                                    H  --                OH NHCH.sub.2 CH.sub.2 OH                                                                  CH.sub.3                                    H  --                OH N-pyrrol- CH.sub.3                                                            idinyl                                                H  --                OH NH.sub.2  H                                           __________________________________________________________________________

                                      TABLE IV                                    __________________________________________________________________________     ##STR18##                                                                                    R.sup.a'                                                      R  R.sup.a'     Position                                                                           T  R.sup.c   R.sup.d                                     __________________________________________________________________________    H  CN           7    OH H         CH.sub.3                                    H  CONH.sub.2   10   OH H         CH.sub.3                                    H  CONMe.sub.2  10   OH H         CH.sub.3                                    H  CHO          10   OH H         CH.sub.3                                    H  SCH.sub.3    10   OH H         CH.sub.3                                    H  SOCH.sub.3   10   OH H         CH.sub.3                                    H  SO.sub.2 CH.sub. 3                                                                         10   OH H         CH.sub.3                                    H  F            10   OH H         CH.sub.3                                    H  SO.sub.2 NH.sub.2                                                                          10   OH H         CH.sub.3                                    H  CH.sub.2 OH  3    OH H         CH.sub.3                                    H  CN           3    OH H         CH.sub.3                                    H  CONH.sub.2   3    OH H         CH.sub.3                                    H  CHO          3    OH H         CH.sub.3                                    H  CH.sub.2 OH  4    OH H         CH.sub.3                                    H  CN           4    OH H         CH.sub.3                                    H  CONH.sub.2   4    OH H         CH.sub.3                                    H  CHO          4    OH H         CH.sub.3                                    H  CN           10   F  H         CH.sub.3                                    H  CHO          10   F  H         CH.sub.3                                    H  CONH.sub.2   10   F  H         CH.sub.3                                    CH.sub.3                                                                         CN           10   OH H         CH.sub.3                                    CH.sub.3                                                                         CONH.sub.2   10   OH H         CH.sub.3                                    CH.sub.3                                                                         CHO          10   OH H         CH.sub.3                                    CH.sub.3                                                                         CN           10   F  H         CH.sub.3                                    H  CN           10   OH H         Et                                          H  CONH.sub.2   10   OH H         Pr                                          H  CONH.sub.2   10   OH H         Bu                                          H  CF.sub.3     3    OH H         CH.sub.3                                    H  OCH.sub.3    2    OH H         CH.sub.3                                    H   OCH.sub.2 CO.sub.2 CH.sub.3                                                               1    OH H         CH.sub.3                                    H  Cl           3,4,10                                                                             OH H         CH.sub.3                                    H  OH           2    OH H         CH.sub.3                                    H  OCOCH.sub.3  3    OH H         CH.sub.3                                    H  OCONH.sub.2  3    OH H         CH.sub.3                                    H  SCH.sub.2 CH.sub.2 OH                                                                      3    OH H         CH.sub.3                                    H  SOCH.sub.2 CH.sub.2 OH                                                                     2    OH H         CH.sub.3                                    H  SCH.sub.2 CONH.sub.2                                                                       10   OH H         CH.sub.3                                    H  SO.sub.2 NMe.sub.2                                                                         10,3 OH H         CH.sub.3                                    H  NHCHO        3    OH H         CH.sub.3                                    H  --                OH NHCH.sub.2 CONH.sub.2                                                                   CH.sub.3                                    H  --                OH N(CH.sub.3).sub.2                                                                       CH.sub.3                                    H  --                F  N(CH.sub.3).sub.2                                                                       CH.sub.3                                    CH.sub.3                                                                         --                OH N(CH.sub.3).sub.2                                                                       CH.sub.3                                    H  CH.sub.2 OH  3    OH H         O.sup.-                                     H  CH.sub.2 OH  3    OH H         NH.sub.2                                    H  CH.sub.2 OH  3    OH H         CH.sub.2 CH.sub.2 OH                        H  CH.sub.2 OH  3    OH H         CH.sub.2 CH.sub.2 CH.sub.2 CN               H  NHCOCH.sub. 3                                                                              2    OH H         CH.sub.3                                    H  NHCOCH.sub.3 1    OH H         CH.sub.3                                    H  NHSO.sub.2 CH.sub.3                                                                        10   OH H         CH.sub.3                                    H  COMe         10   OH H         CH.sub.3                                    H  COCH.sub.2 OH                                                                              4    OH H         CH.sub.3                                    H  CHNOH        3    OH H         CH.sub.3                                    H  CHNOMe       4    OH H         CH.sub.3                                    H  CHNOCH.sub.2 CO.sub.2 Me                                                                   3    OH H         CH.sub.3                                    H  CHNOCM.sub.e2 CO.sub.2 Me                                                                  3    OH H         CH.sub.3                                    H  CHNOCMe.sub.2 CONH.sub.2                                                                   2    OH H         CH.sub.3                                    H  CO.sub.2 CH.sub.2 CH.sub.2 OH                                                              1    OH H         CH.sub.3                                    H  CONHCH.sub.3 10   OH H         CH.sub.3                                    H  CONHCH.sub.2 CN                                                                            10   OH H         CH.sub.3                                    H  CONHCH.sub.2 CN                                                                            10   F  H         CH.sub.3                                    CH.sub.3                                                                         CONHCH.sub.2 CN                                                                            10   OH H         CH.sub.3                                    H  CONHCH.sub.2 CONH.sub.2                                                                    3    OH H         CH.sub.3                                    H  CONHCH.sub.2 CO.sub.2 CH.sub.3                                                             2    OH H         CH.sub.3                                    H  CONHOH       10   OH H         CH.sub.3                                    H  CONHOCH.sub.3                                                                              1    OH H         CH.sub.3                                    H  CO.sub.2 CH.sub. 3                                                                         10   OH H         CH.sub.3                                    tetrazol4l                                                                       3            OH   H  CH.sub.3                                              H  SCF.sub.3    10   OH H         CH.sub.3                                    H  PO.sub.2 NH.sub.2                                                                          10   OH H         CH.sub.3                                    H  CONHSO.sub.2 Ph                                                                            10   OH H         CH.sub.3                                    H  CONHSO.sub.2 NH.sub.2                                                                      10   OH H         CH.sub.3                                    H  SO.sub.2 CF.sub.3                                                                          3    OH H         CH.sub.3                                    H  SO.sub.2 NHCN                                                                              10   OH H         CH.sub.3                                    H  SO.sub.2 NHCONH.sub.2                                                                      10   OH H         CH.sub.3                                    H  CHCHCN       10   OH H         CH.sub.3                                    H  CHCHCONH.sub.2                                                                             10   OH H         CH.sub.3                                    H  CCCN         10   OH H         CH.sub.3                                    H  CH.sub.2 N.sub.3                                                                           4    OH H         CH.sub.3                                    H  CH.sub.2 CO.sub.2 Me                                                                       1    OH H         CH.sub.3                                    H  SO.sub.2 CH.sub.2 CH.sub.2 OH                                                              10   OH H         CH.sub.3                                    H  CH.sub.2 I   3    OH H         CH.sub.3                                    H  I            10   OH H         CH.sub.3                                    H  Br           10   OH H         CH.sub.3                                    H  --                OH H         CH.sub.2 CH.sub.2 CH.sub.3                  H  --                OH OCH.sub.3 CH.sub.3                                    H  --                OH NHCH.sub.2 CH.sub.2 OH                                                                  CH.sub.3                                    H  --                OH N-pyrrol- CH.sub.3                                                            idinyl                                                H  --                OH NH.sub.2  H                                           __________________________________________________________________________

The carbapenem compounds of the present invention are useful per se andin their pharmaceutically acceptable salt and ester forms in thetreatment of bacterial infections in animal and human subjects. The term"pharmaceutically acceptable ester or salt" refers to those salt andester forms of the compounds of the present invention which would beapparent to the pharmaceutical chemist, i.e. , those which are non-toxicand which would favorably affect the pharmacokinetic properties of saidcompounds, their palatability, absorption, distribution, metabolism andexcretion. Other factors, more practical in nature, which are alsoimportant in the selection, are cost of the raw materials, ease ofcrystallization, yield, stability, hygroscopicity, and flowability ofthe resulting bulk drug. Conveniently, pharmaceutical compositions maybe prepared from the active ingredients in combination withpharmaceutically acceptable carriers. Thus, the present invention isalso concerned with pharmaceutical compositions and methods of treatingbacterial infections utilizing as an active ingredient the novelcarbapenem compounds of the present invention.

The pharmaceutically acceptable salts referred to above may take theform --COOM. The M may be an alkali metal cation such as sodium orpotassium. Other pharmaceutically acceptable cations for M may becalcium, magnesium, zinc, ammonium, or alkylammonium cations such astetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium,meglumine, triethanolhydroammonium, etc.

The pharmaceutical acceptable esters of the novel carbapenem compoundsof the present invention are such as would be readily apparent to amedicinal chemist, and include, for example, those described in detailin U.S. Pat. No. 4,309,438, Column 9, line 61 to Column 12, line 51,which is incorporated herein by reference. Included within suchpharmaceutically acceptable esters are those which are hydrolyzed underphysiological conditions, such as pivaloyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl, and those described in detail inU.S. Pat. No. 4,479,947, which is incorporated herein by reference.

The novel carbapenem compounds of the present invention may take theform COOM, where M is a readily removable carboxyl protecting group.Such conventional blocking groups consist of known ester groups whichare used to protectively block the carboxyl group during the synthesisprocedures described above. These conventional blocking groups arereadily removable, i.e., they can be removed, if desired, by procedureswhich will not cause cleavage or other disruption of the remainingportions of the molecule. Such procedures include chemical and enzymatichydrolysis, treatment with chemical reducing or oxidizing agents undermild conditions, treatment with a transition metal catalyst and anucleophile, and catalytic hydrogenation. Examples of such esterprotecting groups include benzhydryl, p-nitrobenzyl, 2-naphthylmethyl,allyl, benzyl, t-butyl, trichloroethyl, silyl such as trimethylsilyl,trimethylsilylethyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl,p-methoxyphenyl and 4-pyridylmethyl.

The compounds of the present invention are valuable antibacterial agentsactive against various Gram-positive and to a lesser extentGram-negative bacteria and accordingly find utility in human andveterinary medicine. The antibacterials of the invention are not limitedto utility as medicaments; they may be used in all manner of industry,for example: additives to animal feed, preservation of food,disinfectants, and in other industrial systems where control ofbacterial growth is desired. For example, they may be employed inaqueous compositions in concentrations ranging from 0.1 to 100 parts ofantibiotic per million parts of solution in order to destroy or inhibitthe growth of harmful bacteria on medical and dental equipment and asbactericides in industrial applications, for example in waterbasedpaints and in the white water of paper mills to inhibit the growth ofharmful bacteria.

The compounds of this invention may be used in any of a variety ofpharmaceutical preparations. They may be employed in capsule, powderform, in liquid solution, or in suspension. They may be administered bya variety of means; those of principal interest include: topically orparenterally by injection (intravenously or intramuscularly).

Compositions for injection, a preferred route of delivery, may beprepared in unit dosage form in ampules, or in multidose containers. Thecompositions may take such forms as suspensions, solutions, or emulsionsin oily or aqueous vehicles, and may contain formulatory agents.Alternatively, the active ingredient may be in powder form forreconstitution, at the time of delivery, with a suitable vehicle, suchas sterile water. Topical applications may be formulated in hydrophobicor hydrophilic bases as ointments, creams, lotions, paints, or powders.

The dosage to be administered depends to a large extent upon thecondition and size of the subject being treated as well as the route andfrequency of administration, the parenteral route by injection beingpreferred for generalized infections. Such matters, however, are left tothe routine discretion of the therapist according to principles oftreatment well known in the antibacterial art. Another factorinfluencing the precise dosage regimen, apart from the nature of theinfection and peculiar identity of the individual being treated, is themolecular weight of the chosen species of this invention.

The compositions for human delivery per unit dosage, whether liquid orsolid, may contain from 0.1% to 99% of active material, the preferredrange being from about 10-60%. The composition will generally containfrom about 15 mg to about 1500 mg of the active ingredient; however, ingeneral, it is preferable to employ a dosage amount in the range of fromabout 250 mg to 1000 mg. In parenteral administration, the unit dosageis usually the pure compound I in sterile water solution or in the formof a soluble powder intended for solution.

The preferred method of administration of the Formula I antibacterialcompounds is parenteral by i.v. infusion, i.v. bolus, or i.m. injection.

For adults, 5-50 mg of Formula I antibacterial compounds per kg of bodyweight given 2, 3, or w times per day is preferred. Preferred dosage is250 mg to 1000 mg of the Formula I antibacterial given two (b.i.d.)three (t.i.d.) or four (q.i.d.) times per day. More specifically, formild infections a dose of 250 mg t.i.d. or q.i.d. is recommended. Formoderate infections against highly susceptible gram positive organisms adose of 500 mg t.i.d. or q.i.d. is recommended. For severe,life-threatening infections against organisms at the upper limits ofsensitivity to the antibiotic, a dose of 1000 mg t.i.d. or q.i.d. isrecommended.

For children, a dose of 5-25 mg/kg of body weight given 2, 3, or 4 timesper day is preferred; a dose of 10 mg/kg t.i.d. or q.i.d. is usuallyrecommended.

Antibacterial compounds of Formula I are of the broad class known ascarbapenems or 1-carbadethiapenems. Naturally occuring carbapenems aresusceptible to attack by a renal enzyme known as dehydropeptidase (DHP).This attack or degradation may reduce the efficacy of the carbapenemantibacterial agent. The compounds of the present invention, on theother hand, are significantly less subject to such attack, and thereforemay not require the use of a DHP inhibitor. However, such use isoptional and contemplated to be part of the present invention.Inhibitors of DHP and their use with carbapenem antibacterial agents aredisclosed in the prior art [see European Patent Applications No.79102616.4 filed Jul. 24, 1979 (Patent No. 0 007 614); and No.82107174.3, filed Aug. 9, 1982 (Publication No. 0 072 014)].

The compounds of the present invention may, where DHP inhibition isdesired or necessary, be combined or used with the appropriate DHPinhibitor as described in the aforesaid patents and publishedapplication. Thus, to the extent that the cited European patentapplications 1.) define the procedure for determining DHP susceptibilityof the present carbapenems and 2.) disclose suitable inhibitors,combination compositions and methods of treatment, they are incorporatedherein by reference. A preferred weight ratio of Formula I compound: DHPinhibitor in the combination compositions is about 1:1. A preferred DHPinhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoicacid or a useful salt thereof.

The invention is further defined by reference to the following examples,which are illustrative and not limiting. All temperatures are in degreesCelsius.

EXAMPLE 1 ##STR19##

Dry nitrogen gas was bubbled through a mixture of 1 (300 mg; 1.16 mmol),hexamethylditin (418 mg; 1.28 mmol; 1.1 equiv.), Pd(PPh₃)₄ (67 mg; 0.058mmol; 5 mol %) and triphenylphosphine (9 mg; 0.035 mmol; 3 mol %) intoluene (6 mL) for 15 minutes. The reaction mixture was then heated toreflux for 1 hr. 45 min. before being poured into Et₂ O. The organiclayers were washed with H₂ O (1×), saturated NaHCO₃ (3×), H₂ O (1×) andbrine (1×). The reaction mixture was dried over MgSO₄, filtered and thesolvent was removed in vacuo. Purification via SiO₂ flash columnchromatography (20% EtOAc/hexanes) provided the stannane 2.

¹ H NMR (200 MHz, CDCl₃) δ0.42 (s, 9H), 7.68-7.75 (m 1H), 7.85-7.92 (m,2H), 8.06 (d, J=7.8 Hz, 1H), 8.17 (d, J=7.9 Hz, 1H), 8.67-8.74 (m, 2H),9.28 (s, 1H).

EXAMPLE 2 ##STR20##

To stannane 2 (96.7 mg; 0.283 mmol), prepared as described in Example 1,in anhydrous CH₂ Cl₂ (1.4 mL) under N₂ at 0° C. was added CH₃ OSO₂ CF₃(35.2 μL; 0.311 mmol; 1.1 eq). The reaction vessel was then allowed toreach ambient temperature and stirred for one hour. A white precipitateformed. Some CHCl₃ was then added to dissolve the precipitate, prior toremoval of the solvents in vacuo to provide Stannane 3.

¹ HNMR (300 MHz, CDCl₃) δ:0.48 (s, 9H), 4.81 (s, 3H), 8.00 (t, J=7.5 Hz,1H), 8.17 (s, 2H), 8.28 (t, J=7.2 Hz, 1H), 8.80 (m, 2H), 8.93 (s, 1H),10.54 (s, 1H).

EXAMPLE 3 ##STR21##

To a stirred solution of the bicyclic β-keto ester 4 (412.9 mg, 1.18mmol) in dry THF (4.9 mL) at -78° C. under N₂ was added diisopropylamine(180 μL, 1.3 mmol, 1.1 eq). The resultant yellow mixture was stirred for10 minutes before trifluoromethanesulfonic anhydride (220 μL, 1.3 mmol,1.1 eq) was added. After 15 minutes the mixture was treated sequentiallywith anhydrous N-methyl-2-pyrrolidinone (4.9 mL), the Pd₂ (dba)₃ •CHCl₃catalyst (24.5 mg, 2.4×10⁻² mmol, 2.0 mol%), the aryl stannane 3 (500mg, 0.988 mmol) and diisopropylammonium chloride (136 mg; 0.988 mmol).The low temperature bath was then removed and the reaction vessel wasplaced in a warm water bath to quickly reach ambient temperature. Theresulting solution was stirred for 45 minutes at ambient temperature.

The reaction mixture was poured into EtOAc and washed repetitively withH₂ O. The H₂ O layer was then back extracted with CH₂ Cl₂. The organiclayers were combined, dried over Na₂ SO₄, filtered and the solvent wasremoved in vacuo. Precipitation from CH₂ Cl₂ /Et₂ O provided carbapenem5.

¹ H NMR (400 MHz, D₆ -Acetone) δ:1.31 (d, J=6.3 Hz, 3H), 3.47-3.54 (m,2H), 3.85 (1/2 ABX, J_(AB) =18.4 Hz, J_(AX) =8.5 Hz, 1H), 4.18-4.25 (m,1H), 4.48-4.52 (m, 1H), 4.95 (s, 3H), 5.32 (AB_(q), J_(AB) =13.7 Hz,Δυ_(AB) =67.2 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.98 (d, J=8.8 Hz, 2H),8.15 (t, J=7.1 Hz, 1H), 8.26 (dd, J=9.0, 1.9 Hz, 1H), 8.41 (t, J=7.1 Hz,1H), 8.62-8.66 (m, 2H), 9.08 (d, J=8.4 Hz, 1H), 9.21 (d, J=1.83 Hz, 1H);IR (CHCl₃)1765, 1720, 1625, 1600, 1515 cm⁻¹.

EXAMPLE 4 ##STR22##(5R,6S)-2-(5-Methyl-2-phenanthiridinyl)-6-(1R-hydroxyethyl)carbapen-2-em-3-carboxylate

To a stirred solution of 5 (50 mg, 0.0072 mmol) and sodium bicarbonatesolution (75.8 μL 0.0072 mmol, 1.0 eq) in 2:1 acetone/H₂ O was added 5%Rh/Al₂ O₃ catalyst (5.0 mg, 10% wt), and the reaction mixture washydrogenated under an H₂ balloon at ambient temperature for 40 minutes.The mixture was then filtered through a pad of celite and the acetonesolvent from the filtrate was removed in vacuo. The remaining water wasthen frozen and lypholized at 0° C. Crude 6 was redissolved in a minimalamount of H₂ O/CH₃ CN and purified using Analtech reverse phaseprep-plates (1.6:1 H₂ O/CH₃ CN) to provide carbapenem 6.

¹ H NMR (400 MHz, 2:1 D₂ O/CD₃ CN) δ1.68 (d, J=6.2 Hz, 3H), 3.68 (1/2ABX, J_(AB) =15.6 Hz, J_(AX) =9.9 Hz, 1H), 3.91-3.94 (m, 1H), 4.00-4.08(m, 1H), 4.60-4.68 (m, 1H), 4.75-4.80 (m, obscured by HOD peak, 1H),5.04 (S, 3H), 8.46 (t, J=7.5 Hz, 1H)8.53 (d, J=9.2 Hz, 1H), 8.70-8.80(m, 2H), 8.74 (d, J=9.2 Hz, 1H), 9.27, (d, J=1.7 Hz, 1H), 9.32 (d, J=8.4Hz, 1H), 10.18 (s, 1H). I.R. (KBr) 1750, 1600 cm⁻¹ U.V. (MOPS BUFFER)λ_(ext) =293 nm, ε_(ext) =3000.

EXAMPLE 5 ##STR23##

To phenanthridine 2, prepared as described in Example 1 (73.2 mg; 0.214mmol) in CH₂ Cl₂ (4.3 mL) cooled to 0° C. under N₂ was added aqueousNaHCO₃ (1.7 mL; 0.214 mmol; 1 equiv) followed by mCPBA (40.6 mg; 0.235mmol; 1.1 eq). After allowing the reaction to stir for 2 hours atambient temperature a 5% aqueous solution of Na₂ S₂ O₃ (5 mL) was added.The reaction mixture was stirred for one hour before being poured intoEt₂ O. The organic layers were washed with H₂ O (1×), brine (2×), driedover MgSO₄, filtered and evaporated. Purification via SiO₂ flash columnchromatography (100% EtOAc→20% MeOH/EtOAc) provided stannane 7.

¹ H NMR (400 MHz, CDCl₃) δ0.42 (s, 9H), 7.66 (t, J=7.8 Hz, 1H),7.73-7.80 (m, 2H), 7.93 (d, J=8.1 Hz, 1H), 8.56 (d, J=8.4 Hz, 1H), 8.68(s, 1H), 8.83 (d, J=8.1 Hz, 1H), 8.90 (s, 1H).

EXAMPLE 6 ##STR24##

To a stirred solution of the bicyclic β-keto ester 4 (116.7 mg, 0.335mmol) in dry THF (1.4 mL) at -78° C. under N₂ was added diisopropylamine(51.6 μL, 0.369 mmol, 1.1 eq). The resultant yellow mixture was stirredfor 10 minutes before trifluoromethanesulfonic anhydride (62 μL, 0.369mmol, 1.1 eq) was added. After 15 minutes the reaction mixture wastreated sequentially with anhydrous N-methyl-2-pyrrolidinone (1.4 mL),the (MeCN)₂ PdCl₂ catalyst (3.6 mg, 1.4×10² mmol, 5.0 mol %), thearyl-stannane 7 (100 mg, 0.279 mmol) and diisopropylammonium chloride(38 mg; 0.279 mmol). The low temperature bath was then removed and thereaction vessel was placed in a warm water bath to quickly reach ambienttemperature. The resulting solution was stirred for 20 minutes atambient temperature.

The reaction was then poured into EtoAc and washed with water (4×) andbrine. The organic layer was dried (Na₂ SO₄), filtered, and evaporatedin vacuo. The residue was dissolved in CH₂ Cl₂ and precipitated with Et₂O to provide carbapenem 8.

¹ H NMR (400 MHz, D₆ DMSO) δ1.19 (d, J=6.0 Hz, 3H) 3.35 (1/2 ABX,obscured by H₂ O peak from DMSO, 1H), 3.49-3.50 (m, 1H), 3.73 (1/2 ABX,J_(AB) =18.9 Hz, J_(AX) =8.6 Hz, 1H), 4.00-4.06 (m, 1H), 4.31-4.35 (m,1H), 5.22 (ABq, J_(AB) =13.6 Hz, Δυ_(AB) =49.8 Hz, 2H), 7.32 (d, J=8.5Hz, 2H), 7.68-7.72 (m, 2H), 7.83 (d, J=8.8 Hz, 2H), 7.93-7.95 (m, 1H),8.58 (d, J=8.7, 1H), 8.62-8.64 (m, 1H), 8.80 (s, 1H), 9.08 (s, 1H); I.R.(KBr) 3520, 1750, 1720, 1600, 1510 cm⁻¹.

EXAMPLE 7 ##STR25##

To a stirred solution of 8 (43.6 mg, 0.083 mmol) and sodium bicarbonatesolution (87 μL, 0.087 mmol, 1.05 eq) in 2:1 -THF/H₂ O was added 10%Pd/C catalyst (4.4 mg, 10% wt), and the reaction mixture washydrogenated under an H₂ balloon at ambient temperature for 40 minutes.The mixture was then filtered through a pad of celite, and the THFsolvent from the filtrate was removed in vacuo. The remaining water wasthen frozen and lyophilized at 0° C. Crude 9 was redissolved in aminimal amount of H₂ O/CH₃ CN and purified using Analtech reverse phaseprep-plates (5:1 H₂ O/CH₃ CN) to provide carbapenem 9.

¹ H NMR (400 MHz, (2:1) D₂ O/CD₃ CN) δ6 1.70 (d, J=6.4 Hz, 3H), 3.64(1/2 ABX, J_(AB) =16.6 Hz, J_(AX) =9.9 Hz, 1H), 3.91 (dd, J=5.9, 2.8 Hz,1H), 4.00 (1/2 ABX, J_(AB) =16.7 Hz, J_(AX) =8.5, 1H), 4.62-4.65 (m,1H), 4.75 (dt, J=9.5, 2.9 Hz, 1H), 8.21 (t, J=7.8 Hz, 1H) 8.32-8.36 (m,2H), 8.43 (d, J=8.0 Hz, 1H), 8.97 (d, J=8.9 Hz, 1H), 9.04-9.07 (m, 2H),9.45 (s, 1H); U.V. (MOPS BUFFER) λ_(ext1), =299 nm, ε_(ext1), =6500;λ_(ext2) =346 nm, λ_(ext2) =5600.

EXAMPLE 8 ##STR26##

To a solution of KCN (90.9 mg; 1.40 mmol; 5 eq) and K₃ Fe(CN)₆ (136.3mg; 0.41 mmol; 1.5 eq) in H₂ O (5.6 mL) and THF (1.0 mL) was addedphenanthridine N-oxide 7. (100 mg; 0.279 mmol). The suspension washeated to reflux for 3 days. The reaction mixture was cooled to ambienttemperature before being poured into Et₂ O and washed with H₂ O (3×) andbrine. The organic layer was dried (MgSO₄) filtered and evaporated.Purification by SiO₂ column chromatography provided stannane 10.

¹ H NMR (400 MHz, CDCl₃) δ0.44 (s, 9H), 7.70-7.79 (m, 2H), 7.93 (d,J=8.0 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 8.54 (d, J=7.7 Hz, 1H), 8.65-8.70(m, 2H); I.R. (CHCl₃)2230, 1560 cm⁻¹.

EXAMPLE 9 ##STR27##

Compound 11 was prepared by the procedure described in Example 6 butsubstituting the stannane 10 prepared as described in Example 8, andemploying 5 mol % (MeCN)₂ PdCl₂ as the catalyst.

¹ H NMR (400 MHz, D₆ Acetone) δ1.30 (d, J=6.3 Hz, 3H), 3.45 (1/2 ABX,J_(AB) =18.2, J_(AX) =10.1, 1H), 3.51 (dd, J=6.4, 2.9 Hz, 1H), 3.79 (1/2ABX, J_(AB) =18.5 Hz, J_(AX) =8.7, 1H), 4.18-4.23 (m, 1H), 4.45-4.50 (m,1H), 5.27 (ABq, J_(AB) =13.4 Hz, Δυ_(AB) =64.7 Hz, 2H), 7.45 (d, J=9.1Hz, 2H), 7.80-8.02 (complex m, 7H), 8.61 (d, J=8.9 Hz, 1H), 8.70 (d,J=8.8 Hz, 1H), 8.88 (d, J=1.7 Hz, 1H); IR (KBr) 3550, 3500-3400, 2230,1750, 1720, 1600, 1515 cm⁻¹.

EXAMPLE 10 ##STR28##

Compound 12 was prepared by the procedure described in Example 7 butsubstituting the carbapenem 11 prepared as described in Example 9, forthe carbapenem 8 and using Pd/C as the catalyst.

¹ H NMR (400 MHz, (2:1) D₂ O/CD₃ CN) δ1.65 (d, J=6.3 Hz, 3H), 3.60 (1/2ABX, J_(AB) =16.4 Hz, J_(AX) =8.8 Hz, 1H), 3.88 (dd, J=6.1, 2.9 Hz, 1H),3.94 (1/2 ABX, J_(AB) =16.6 Hz, J_(AX) =8.5 Hz, 1H), 4.53-4.61 (m, 1H),4.72 (dt, J=9.7, 2.9 Hz, 1H), 8.20-8.30 (complex m, 3H), 8.37-8.41 (m,1H), 8.87 (d, J=9.0 Hz, 1H), 8.87-8.90 (m, 2H); IR (KBr)1750, 1600 cm⁻¹; UV (MOPS buffer) λ_(ext) =305 nm, ε_(ext) =5600.

EXAMPLE 11 ##STR29##

To a stirred solution of 13 (200 mg, 0.77 mmol) in concentrated sulfuricacid (12.9 mL) at 0° C. was added a solution of sodium azide (75.3 mg,1.16 mmol, 1.5 eq) in water (1 mL). After stirring the resultant blackmixture for 24 hours at room temperature, ice-water (10 mL) was added.The reaction mixture was then stirred for 15 minutes, poured into ethylacetate (200 mL), and washed with saturated sodium bicarbonate solution(2×25 mL), water (2×), and brine. The organic layer was dried (MgSO₄),filtered, and evaporated in vacuo to obtain a mixture of 1:1 inseparablebromo-phenanthridone isomers (14 and 15) in 74% yield (156 mg).

EXAMPLE 12 ##STR30##

A suspension of 13 (200 mg, 0.77 mmol) and hydroxylamine hydrochloride(161 mg, 2.32 mmol, 3.0 eq) in anhydrous pyridine (7.7 mL) was sonicatedto afford dissolution. The homogeneous mixture was then stirred at roomtemperature for 3.5 hour and poured into ether (100 mL). The ethereallayer was washed with water (1×), 1N HCl solution (4×15 mL), saturatedsodium bicarbonate solution (2×15 mL), water (2×), and brine. Theorganic layer was dried (MgSO₄), filtered, and evaporated in vacuo toafford 200 mg (95%) of the hydroxylamine isomers 16, a white solid. [Thehydroxylamine isomers mixture 16 was not separated or characterized andwas taken to the next step].

A mixture of 16 (104 mg, 0.38 mmol) in an excess amount ofpolyphosphoric acid (9g) was heated to 200° C. After 30 minutes theresultant black paste was dissolved in ice-water (50 mL) and extractedwith ethyl acetate (3×50 mL). The combined organic layers were thenwashed with saturated sodium bicarbonate solution (3×25 mL), water (2×),and brine. The organic layer was dried (MgSO₄), filtered, and evaporatedin vacuo. The inseparable 1:1 mixture of the phenanthridone isomers (14and 15) was isolated in 96% yield (100 mg) as a beige solid.

¹ H-NMR for 14/15 [300 MHz, D₆ DMSO, mixture]: δ7.24 to 7.38 (m, 3H),7.52 (t, J=6.9 Hz, 1H), 7.64 to 7.71 (m, 2H), 7.79 to 7.89 (m, 2H), 8.22(d, J=8.5 Hz, 1H), 8.32 (d, J=7.4 Hz, 1H), 8.45 (d, J=7.8 Hz, 1H), 8.56to 8.60 (m, 2H), 8.75 (s, 1H). IR (KBr): 3020, 2880, 1685, 1610 cm⁻¹.Fast atom bombardment mass spectrum: m/e 274, 276 (calculated MH+ C₁₃ H₈BrNO=274, 276).

EXAMPLE 13 ##STR31##

Chlorotrimethylsilane (10.4 mL, 81.9 mmol, 3.0 eq) was added to astirred solution of 17 (7.0 g, 27.3 mmol) in dry THF (103 mL) at -78° C.under N₂. Tert-butyllithium (23.1 mL, 30 mmol, 1.1 eq) was addeddropwise at -78° C. over 45 minutes. The reaction mixture was warmed to0° C. with an ice bath and then quenched with saturated ammoniumchloride solution (25 mL). After removal of THF in vacuo the reactionmixture was poured into ether (400 mL) and washed with water, saturatedsodium bicarbonate solution (2×50 mL), water, and brine. The ethereallayer was dried (MgSO₄), filtered, and evaporated in vacuo. Purificationusing flash chromatography (20% EtOAc/hex) afforded 5.7 g (87%) of arylsilane 18, a white solid.

¹ H-NMR for 18 [400 MHz, CDCl₃, rotamers]: δ0.24 (s, 9H), 1.08 (broad s,3H), 1.21 (broad s, 3H), 3.23 (broad s, 2H), 3.51 (broad s, 2H), 7.30(d, J=8.1 Hz, 2H), 7.50 (d, J=8.1 Hz, 2H). IR(CHCl₃): 3010, 1615 cm⁻¹.

EXAMPLE 14 ##STR32##

To a stirred solution of N,N,N',N'-tetramethylethylenediamine (2.7 mL,17.6 mmol, 1.1 eq) in anhydrous THF (100 mL) at -78° C. under N₂ wasadded dropwise sec-butyllithium (13.0 mL, 16.8 mmol, 1.05 eq). After 15minutes the yellow mixture was treated with a solution of 18 (4.0 g,16.0 mmol) in dry THF (40 mL), and the resultant red mixture was stirredfor 1 hour at -78° C. Trimethylborate (2.0 mL, 17.6 mmol, 1.1 eq) wasadded dropwise. The reaction flask was warmed to 0° C. with an ice bathand then stirred for 5 minutes. The green reaction mixture was quenchedwith 8% HCl solution (60 mL), stirred for 10 minutes, and the organicsolvent concentrated in vacuo. The mixture was poured into ether and theethereal layer was washed with water (2×), brine, dried (MgSO₄),filtered, and evaporated in vacuo. Purification using flashchromatography (5:3:1 EtOAc/acetone/H₂ O) provided 3.77 g (80%) ofboronic acid 19, a white foam.

¹ H-NMR for 19 [200 MHz, CDCl₃, rotamers]: δ0.27 (s, 9H), 0.88 to 1.16(m, 6H), 3.27 to 3.36 (m, 4H), 7.28 (d, J=6.4 Hz, 1H), 7.52 (d, J=7.6Hz, 1H), 8.15 (s, 1H). IR(CHCl₃): 2960, 1615, 1601 cm⁻¹.

EXAMPLE 15 ##STR33##

Aqueous sodium carbonate (2.66 mL, 5.32 mmol, 2.0 eq) was added to astirred solution of 19 (779.3 mg, 2.7 mmol) andtetrakis(triphenylphosphine) palladium (O) (153.7 mg, 5.0 mol %) intoluene (10.6 mL). The resulting two-phase mixture was stirred for 10minutes under N₂ at room temperature. A solution of 20 (590.5 g, 9.6mmol, 1.1 eq) dissolved in absolute ethanol (5 mL) was added, and theheterogeneous mixture was stirred for 3 hours at reflux under N₂. Thecooled reaction mixture was poured into ether (175 mL) and washed withwater (1×), saturated sodium carbonate solution (2×25 mL), water (1×),and brine. The organic layer was dried (MgSO₄), filtered, and evaporatedin vacuo. Purification using flash chromatography (60% EtOAc/hex)provided 812.5 mg (82.5%) of the biphenyl compound 21, a yellow foam.

¹ H-NMR for 21 [400 MHz, CDCl₃, rotamers]; δ0.24 (s, 9H), 0.80(t, J=7.1Hz, 3H), 0.91(t, J=7.1 Hz, 3H), 2.80 to 3.67 (broad, 4H), 7.30 to 7.33(m, 2H), 7.46 (t, J=8.1 Hz, 1H), 7.52 to 7.58 (m, 3H), 7.90 (d, J=8.8Hz, 1H). IR (CHCl₃): 3000, 2980, 1610, 1580, 1525 cm⁻¹.

EXAMPLE 16 ##STR34##

Iodine monochloride in dichloromethane (10.9 mL, 10.9 mmol, 5.0 eq) wasadded dropwise over 0.5 hour to a stirred solution of 21 (812.5 mg, 2.19mmol) in dry dichloromethane (10.9 mL). The reaction mixture was thenpoured in ether (200mL) and washed with saturated sodium thiosulfatesolution (2×25 mL), water, saturated bicarbonate solution (2×25 mL),water and brine. The etheral layer was then dried (MgSO₄), filtered, andevaporated in vacuo. Purification using flash column chromatography (30%EtOAc/hex) afforded 887.7 mg (95.4%) of 22, a yellow foam.

¹ H-NMR for 22 [400 MHz, CDCl₃, rotamers]: δ0.75 (t, J=7.0 Hz, 3H), 0.93(t, J=7.0 Hz, 3H), 2.82 to 3.60 (broad, 4H), 7.07 (d, J=8.1 Hz, 1H),7.46 to 7.51 (m, 2H), 7.56 to 7.60 (m, 2H), 7.73 (d, J=8.1 Hz, 1H), 7.97(d, J=8.1 Hz, 1H). IR (CHCl₃): 3000, 2980, 1620, 1580, 1525 cm⁻¹.

EXAMPLE 17 ##STR35##

To a stirred solution of 22 (158.0 mg, 0.37 mmol) in 3:2:2 AcOH/EtOH/THF(7.0 mL) was added iron powder (103.8 mg, 1.86 mmol, 5.0 eq), and thereaction mixture was stirred at reflux until a white solid had separated(30 minutes). The reaction mixture was poured into ethyl acetate (200mL) and washed with saturated sodium bicarbonate solution (1×25 mL),water, and brine. The organic layer was dried (MgSO₄) filtered andevaporated in vacuo. Chloroform (˜10 mL) was added and the product wasfiltered to afford 119.0 mg (99.5%) of 23, a white solid.

¹ H-NMR for 23 [400 MHz, D₆ DMSO]: δ7.24 (t, J=7.7 Hz, 1H), 7.34 (d,J=8.1 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 8.42 (d, J=8.1 Hz, 1H), 8.89 (s,1H). IR(KBr): 3010, 2990, 2870, 1665, 1600, 1585 cm⁻¹.

EXAMPLE 18 ##STR36##

To phenanthridone 23 (50 mg; 0.156 mmol) and PCl₅ (32.5 mg; 0.156 mmol;1.0 eq) was added excess POCl₃ (2.5 mL). The reaction was heated toreflux for 5 hours, cooled and quenched by pouring onto ice. The aqueouslayer was extracted with CHCl₃. The organic layer was dried over MgSO₄,filtered and evaporated to provide phenanthridine 24 slightlycontaminated with some starting material 23.

¹ H NMR(400 MHz, CDCl₃) δ7.69 (dt, J=8.2, 1.3 Hz, 1H), 7.76 (dt, J=7.2,1.4 Hz, 1H), 8.02-8.08 (m, 2H), 8.16 (d, 8.8 Hz, 1H), 8.45 (d, 7.1 Hz,1H), 8.97 (d, J=1.6 Hz, 1H)

EXAMPLE 19 ##STR37##

To phenanthridine 24 (170 mg; 0.50 mmol) in toluene (5 mL) was added Me₃SnSnMe₃ (180 mg; 0.55 mmol; 1.1 eq), Pd(PPh₃)₄ (29 mg; 0.025 mmol; 5 mol%) and triphenylphosphine (3.9 mg; 0.015 mmol; 3 mol %). After bubblingN₂ through the reaction mixture for 15 minutes, the vessel was heated toreflux for 3 hours. The reaction was cooled, poured into Et₂ O andwashed with H₂ O (1×), saturated NaHCO₃ solution (1×), H₂ O (2×) andbrine. The organic layer was dried (MgSO₄), filtered and evaporated.Purification by flash chromatography (20% EtOAc/hex) provided 25.

¹ H NMR (400 MHz, CDCl₃) δ0.42 (s, 9H), 7.65-7.75 (m, 2H), 7.81 (d,J=7.7 Hz, 1H), 7.96 (d, J=7.7 Hz, 1H), 8.17 (dd, J=8.1, 1.3 Hz, 1H),8.63 (dd, 8.1, 1.4 Hz, 1H), 8.74 (s, 1H), 9.25 (s, 1H).

EXAMPLE 20 ##STR38##

Compound 26 was prepared by the procedure described in Example 2 butsubstituting the stannane 25, obtained as described in Example 19, forstannane 2. ¹ H NMR (400 MHz, CDCl₃) δ0.48 (s, 9H), 4.82 (s, 3H),8.03-8.09 (m, 3H), 8.13 (d, J=7.8 Hz, 1H), 8.29 (d, J=7.9 Hz, 1H), 8.61(d, J=8.0 Hz, 1H), 8.87 (s, 1H), 8.90 (d, J=7.4 Hz, 1H), 10.46 (s, 1H).

EXAMPLE 21 ##STR39##

Compound 27 was prepared by the method described in Example 3 butsubstituting the stannane 26, obtained as described in Example 20, forstannane 3. ¹ H NMR (400 MHz, D₆ -Acetone) δ1.30 (d, J=6.2 Hz, 3H), 3.50(1/2 ABX, J_(AB) =18.2 Hz, J_(AX) =10.2 Hz, 1H), 3.56 (dd, J=6.2, 3.2Hz, 1H), 3.91 (1/2 ABX, J_(AB) =18.3 Hz, J_(AX) =8.4 Hz, 1H), 4.19-4.23(m, 1H), 4 .49-4.55 (m, 1H), 4.91 (s, 3H), 5.61 (ABq, J_(AB) =13.6 Hz,Δυ_(AB=) 71.7 Hz, 2H), 7.47 (d, J=8.7 Hz, 2H), 7.91 (d, J=8.8 Hz, 2H),8.09-8.22 (complex m, 3H), 8.59-8.63 (m, 2 H), 9.08 (d, J=8.1 Hz, 1H),9.12 (s, 1H), 10.26 (s, 1H); IR (KBr) 3680-3200, 1775, 1720, 1625, 1600,1520 cm⁻¹ ; UV (CH₃ CN) λ=374 nm; ε=13,000.

EXAMPLE 22 ##STR40## (5R, 6S)-2-(5-Methyl-9-phenanthridinyl)-6-(1R-hydroxyethyl)carbapen-2-em-3-carboxylate

Carbapenem 28 was prepared by the procedure described in Example 4, butsubstituting the carbapenem 27, obtained as described in Example 21, forcarbapenem 5. ¹ H NMR (400 MHz (2:1) D₂ O/CD₃ CN) δ1.74 (d, J=6.2 Hz,3H), 3.72 (1/2 ABX, J_(AB) =16.4 Hz, J_(AX) =9.8 Hz, 1H), 3.98-4.02 (m,2H), 4.10 (1/2 ABX, J_(AB) =16.5 Hz, J_(AX) =11.0 Hz, 1H), 4.62-4.70 (m,1H), 4.8-4.85 (obscured by HOD peak, 1H), 5.05 (s, 3H), 8.48 (d, J=8.3Hz, 1H), 8.50-8.59 (complex m, 2H), 8.82 (d, J=8.3 Hz, 2H), 9.21 (s,1H), 9.40 (d, J=7.4 Hz, 1H), 10.16 (s, 1H); I.R. (KBr) 1760, 1600 cm⁻¹ ;U.V. (MOPS BUFFER) λ_(ext) =390 nm, ε_(ext) =6800.

EXAMPLE 23 ##STR41##

To a stirred solution of 4-bromo-3-nitrobenzoic acid (5.0 g, 20.3 mmol)in dry THF (40.6 mL) under N₂ at room temperature was added dropwise theborane-tetrahydrofuran complex (40.6 mL, 40.6 mmol, 2.0 eq). Afterstirring at reflux for 1 hour the reaction mixture was quenched withdropwise addition of triethylamine (1 mL) in methanol (50 mL) at 0° C.The solvent was then removed in vacuo to give crude 4. Purificationusing flash chromatography (30% EtOAc/hex) provided 4.5 g (96%) of 29,an off-white solid.

¹ H-NMR for 29 [400 MHz, CDCl₃ ]: δ1.86 (t, J=5.8 Hz, 1H), 4.74 (d,J=5.8 Hz, 2H), 7.41 (dd, J=8.3, 2.1 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H),7.85 (s, 1H). IR(CHCl₃): 3605, 3500 to 3200, 3010, 2880, 1605, 1535,1355 cm⁻¹.

EXAMPLE 24 ##STR42##

Aqueous sodium carbonate (8.7 mL, 17.4 mmol, 2.0 eq) was added to astirred solution of 19 (2.0 g, 8.7 mmol) andtetrakis(triphenylphosphine)palladium (O) (502.8 mg, 5.0 mol %) intoluene (33.5 mL). The resulting two-phase mixture was stirred for 10minutes under N₂ at room temperature. A solution of 29 (2.8 g, 9.6 mmol,1.1 eq) dissolved in absolute ethanol (9.6 mL) was added, and theheterogeneous mixture was stirred for 3 hours at reflux under N₂. Thecooled reaction mixture was poured into ether (175 mL) and washed withwater (1×), saturated sodium carbonate solution (2×25 mL), water (1×),and brine. The organic layer was dried (MgSO₄), filtered, and evaporatedin vacuo. Purification using flash chromatography (60% EtOAc/hex)provided 2.9 g (83%) of the biphenyl compound 29a, a yellow foam.

¹ H-NMR for 29a [400 MHz, CDCl₃, rotamers]: δ0.24 (s, 9H), 0.87 (t,J=7.1 Hz, 3H), 0.94 (t, J=7.1 Hz, 3H), 2.40 (broad s, 1H), 2.72 to 3.65(broad, 4H), 4.76 (s, 2H), 7.30 to 7.32 (m, 2H), 7.51 to 7.56 (m, 3H),7.93 (s, 1H). IR(CHCl₃): 3360, 3520 to 3300, 2990, 1620, 1605, 1530cm⁻¹.

EXAMPLE 25 ##STR43##

Acetic anhydride (6.8 mL, 72.4 mmol, 10.0 eq) was added to a stirredsolution of 29a (2.9 g, 7.24 mmol) in dry pyridine (36 mL). The reactionmixture was stirred for 25 minutes at room temperature under N₂. Thesolvent was removed in vacuo and the residual oil azeotroped fromtoluene. The crude acetate was redissolved in dry dichloromethane (20mL), and a 1.0M solution of iodine monochloride in dichloromethane (33mL, 33.3 mmol, 4.6 eq) was added dropwise over 1 hour using an additionfunnel. The reaction mixture was then poured into ether (250 mL) and theorganic layer was washed with saturated sodium thiosulfate solution(3×30 mL), water (1×), saturated sodium bicarbonate solution (1×30 mL),water (1×), and brine. The organic layer was dried (MgSO₄), filtered,and evaporated in vacuo to afford 3.6 g (quantitative yield) of 30, ayellow oil.

¹ H-NMR for 30 [400 MHz, CDCl₃, rotamers]: δ0.81 (t, J=7.1 Hz, 3H), 0.98(t, J=7.1 Hz, 3H), 2.14 (s, 3H), 2.78 to 3.65 (broad, 4H), 5.17 (s, 2H),7.08 (d, J=8.1 Hz, 1H), 7.49 to 7.61 (m, 3H), 7.76 (d, J=8.0 Hz, 1H),7.97 (s, 1H). IR(CHCl₃): 3010, 1745, 1610, 1530 cm⁻¹.

EXAMPLE 26 ##STR44##

A solution of 25% sodium methoxide in methanol (0.53 mL, 2.4 mmol, 1.1eq) was added to a stirred solution of 30(1.1 g, 2.2 mmol) in drymethanol (11.0 mL). The reaction mixture was stirred for 10 minutes atroom temperature under N₂. Acetic acid (6.0 mL) and dry tetrahydrofuran(11.0 mL) were then added. Iron powder (371.9 mg, 6.7 mmol, 3.0 eq) wasadded next, and the reaction mixture was stirred at reflux until a whitesolid had separated (approximately 15 minutes). The reaction mixture wascooled, poured into ice water (250 mL), and the solid filtered. Thecrude cyclized product was redissolved in hot ethanol (250 mL), filteredthrough a hot-sintered glass funnel, and the solvent removed in vacuo.Recrystallization from ethanol provided 501 mg (64%) of the cyclizedamide 31, a white fluffy solid.

¹ H-NMR for 31 [400 MHz, d₆ -DMSO]: δ4.57 (s, 2H), 5.36 (t, J=5.7 Hz,1H), 7.16 (d, J=8.2 Hz, 1H), 7.33 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 8.00(d, J=8.4 Hz, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.85 (s, 1H), 11.74 (s, 1H).IR (KBr): 1670, 1601 cm⁻¹.

EXAMPLE 27 ##STR45##2-iodo-8-(t-butyldiphenylsilyloxymethyl)-phenanthridone

To a solution of 2-iodo-8-(hydroxymethyl) phenanthridone 31 andt-butyldiphenylsilyl chloride in CH₂ Cl₂ and THF are added triethylaminefollowed by 4-dimethylaminopyridine. After stirring at room temperatureuntil chromatographic analysis indicates complete reaction, the solutionis poured into ethyl ether and washed successively with sat. NAHCO₃, H₂O, and brine. Drying (Na₂ SO₄) and evaporation provides the crudeproduct which is purified by flash chromatography to provide the titlecompound 32.

EXAMPLE 28 ##STR46##

To a mixture of phenanthridone 32 and PCl₅ is added a molar excess ofPOCl₃. The reaction is heated to reflux until chromatographic analysisindicates complete reaction, cooled and quenched by pouring onto ice.The aqueous layer is extracted with CHCl₃. The organic layer is driedover MgSO₄, filtered and evaporated to provide phenanthridine 33.

EXAMPLE 29 ##STR47##

To a solution of phenanthridine 33 in toluene is added Me₃ SnSnMe₃,Pd(PPh₃)₄ and triphenyl phosphine. After N₂ is bubbled through thereaction mixture for 15 minutes, the vessel is heated to reflux untilchromatographic analysis indicates complete reaction. The reaction iscooled, poured into ether and the organic solution is washed with H₂ O(1×), saturated NaHCO₃ solution (1×), H₂ O (2×) and brine. The organiclayer is dried over MgSO₄, filtered and evaporated to provide the crudeproduct. The crude product is purified by flash chromatography toprovide the compound 34.

EXAMPLE 30 ##STR48##

To a solution of the phenanthridine 34 is THF is added a 1.0M solutionof nBu₄ NF in THF. The reaction solution is stirred untilchromatographic analysis indicates complete reaction and then pouredinto EtOAC. The organic solution is washed with saturated aqueous NaHCO₃(2×) and brine, then is dried over MgSO₄ and filtered. The solution isconcentrated in vacuo and purified by flash chromatography to providethe phenanthridine 35.

EXAMPLE 31 ##STR49##

Employing the procedure described in Example 2, but substituting thehydroxymethylphenanthridinyl stannane 35 prepared as described inExample 30 for the stannane 2, provides the N-methylhydroxymethylphenanthridinyl stannane 36.

EXAMPLE 32 ##STR50##

Employing the procedure described in Example 3, but substituting theN-methyl hydroxymethylphenanthridinyl stannane 36 prepared as describedin Example 31 for the stannane 2, provides the carbapenem 37.

EXAMPLE 33 ##STR51##

Employing the procedure described in Example 4, but substituting the5-methyl-3-hydroxymethylphenanthridinyl carbapenem 37 prepared asdescribed in Example 32 for the carbapenem 5, provides the carbapenem38.

EXAMPLE 34 ##STR52##

Employing the procedure described in Example 5, but substituting thehydroxymethylphenanthridinyl stannane 35 prepared as described inExample 30 for the stannane 2, provides the hydroxymethylphenanthridinylN-oxide 39.

EXAMPLE 35 ##STR53##

Employing the procedure described in Example 3, but substituting theN-methyl hydroxymethylphenanthridinyl stannane 39 prepared as describedin Example 34 for the stannane 3, provides the carbapenem 40.

EXAMPLE 36 ##STR54##

Employing the procedure described in Example 4, but substituting the5-methyl-3-hydroxymethylphenanthridinyl carbapenem 40 prepared asdescribed in Example 35 for the carbapenem 5, provides the carbapenem41.

EXAMPLE 37 ##STR55##

Following the procedure described in Example 18, but substituting2-bromophenanthridone, obtained by the procedure described by L. W.Mosby, J. Chem. Soc., Vol. 76, pp 936(1954), for the iodo phenanthridone23, phenanthridine 42 was obtained.

¹ H NMR (400 MHz, CDCl₃) δ7.77-7.85 (m, 2H), 7.89-7.96 (m, 2H), 8.48 (d,J=7.9 Hz, 1H), 8.53 (d, J=8.1 Hz, 1H), 8.65 (d, J=2.0 Hz, 1H).

EXAMPLE 38 ##STR56##

To a mixture of 42 (600 mg; 2.05 mmol) and ground 4 Å molecular sievesin anhydrous DME was added amino dimethylacetaldehyde (1.2 mL; 10.3mmol; 5 equiv). The mixture was heated at 100° C. for 2 days. Aftercooling, the reaction mixture was poured into EtOAc and washed with H₂ O(1×), 1N HCl (3×), H₂ O (1×), saturated NaHCO₃ solution (1×), H₂ O (2×)and brine. The organic layer was dried (MgSO₄), filtered and the solventremoved in vacuo. Purification via SiO₂ flash column chromotography (30%EtOAc/Hex) afforded compound 43.

¹ H NMR (400 MHz, CDCl₃) δ3.47 (s, 6H), 3.89 (dd, J₁ =J₂ =5.4 Hz, 2H),4.68 (dd, J₁ =J₂ =5.2 Hz, 1H), 5.58-5.68 (b, 1H), 7.55-7.65 (m, 3H),7.76 (t, J=7.1 Hz, 1H) 7.85 (d, J=7.0 Hz, 1H), 8.41-8.43 (m, 2H); IR(CHCl₃) 3470, 1590 cm⁻¹.

EXAMPLE 39 ##STR57##

Compound 43 (308 mg; 0.853 mmol) was dissolved in 5N HCl (30 mL) andheated to reflux overnight. The resulting homogeneous solution wascooled to ambient temperature and poured onto crushed ice. The pH of thesolution was adjusted to 7-8 using 50% NaOH solution. Followingextraction with EtOAc, the organic layer was dried (MgSO₄), filtered andevaporated. The residual oil was purified via SiO₂ flash columnchromatography (100% EtOAc) to afford compound 44.

¹ H NMR (200 MHz CDCl₃) δ7.60-7.75 (complex m, 5H), 7.95 (d, J=1.4 Hz,1H), 8.25-8.35 (m, 1H), 8.57 (d, J=1.6 Hz, 1H), 8.63-8.68 (m, 1H); 1R(CHCl₃) 3000-2920, 1545 cm⁻¹.

EXAMPLE 40 ##STR58##

Following the procedure described in Example 1, but substituting arylbromide 44 for aryl bromide 1, compound 45 was obtained.

¹ H NMR (500 MHz, CDCl₃) δ0.40 (s, 9H), 7.59 (s, 1H), 7.61-7.63 (m, 2H),7.69 (d, J=8.0 Hz, 1H) 7.81 (d, J=8 Hz, 1H), 7.97 (s, 1H), 8.41-8.43 (m,1H), 8.54 (s, 1H), 8.67 (m, 1H); IR (CHCl₃) 2970, 1590, 1525 cm⁻¹.

EXAMPLE 41 ##STR59##

Following the procedure described in Example 2, but substituting arylbromide 45 for aryl bromide 2, provided compound 45.

¹ H NMR (200 MHz, D₆ Acetone) δ0.47 (s, 9H), 4.76 (s 3H), 7.90-8.20(complex m, 3H), 8.36 (d, J=2.3 Hz, 1H), 8.58 (d, J=8.2 Hz, 1H), 8.96(d, J=9.2 Hz, 1H), 9.08-9.18 (m, 3H); IR (CHCl₃) 1600 cm⁻¹.

EXAMPLE 42 ##STR60##

Employing the procedure described in Example 3, but substituting thestannane 46 for the aryl stannane 3, and using the activated ADC-13intermediate in 1.5 molar excess, together with 2 mol % of Pd₂ (DBA)₃•CHCl₃ and 1.0 equivalents of DIPA•HCl, provided compound 46.

¹ H NMR (400 MHz, CDCl₃) δ0.15 (s, 9H), 1.30 (d, J=6.1 Hz, 3H), 3.34(dd, J=18.6, 10.2 Hz, 1H), 3.41 (dd, J=5.4, 3.0 Hz, 1H), 3.52, (dd,J=19.5, 10.0 Hz, 1H), 4.23-4.30 (m, 1H), 4.35-4.42 (m, 1H), 4.49 (s,1H), 5.26 (ABq, J_(AB) =15.6 Hz, ΔυAB=66.7 Hz, 2H), 7.45 (d, J=8.8 Hz,2H), 7.78-7.87 (m, 2H), 7.90-7.96 (m, 3H), 8.04 (d, J=2.1 Hz, 1H), 8.30(d, J=8.8 Hz, 1H), 8.45-8.52 (m, 2H), 8.58 (s, 1H), 8.74 (d, J=2.2 Hz,1H); IR (CHCl₃) 1780, 1720, 1608, 1520 cm⁻¹.

EXAMPLE 43 ##STR61##

Following the procedure described in Example 4, but substitutingcarbapenem 46 for carbapenem 5, and using 5% Rh/Al₂ O₃ as the catalystand EtOH/THF/H₂ O as the solvent system, provided carbapenem 47.

¹ H NMR (400 MHz, D₆ DMSO/D₂ O) δ1.18 (d, J=6.4 Hz, 2H), 3.14 (dd,J=15.6, 10.2 Hz, 1H), 3.26 (dd, J=6.2, 3.9 Hz, 1H), 3.32 (dd, J=16.9,8.3 Hz, 1H), 3.92-3.99 (m, 1H), 4.12-4.17 (m, 1H), 4.44 (s, 3H),7.89-7.92 (m, 1H), 7.97 (d, J=8.4 Hz, 1H), 8.03 (t, J=7.51 Hz, 1H), 8.25(s, 1H), 8.37 (d, J=8.8 Hz, 1H), 8.72 (d, J=8.1 Hz, 1H), 8.81 (d, J=8.0Hz, 1H), 8.93 (s, 1H), 9.05 (s, 1H); IR (KBr) 1750, 1600 cm⁻¹ ; UV (MOPSBUFFER λ_(ext1) =327 nm, ε_(ext1) 32 4000; λ_(ext2) =343 nm, ε_(ext2) 323200.

What is claimed is:
 1. A compound of the formula: ##STR62## wherein Y is##STR63## R is H or CH₃ ; R¹ and R² are independently H, CH₃ --, CH₃ CH₂--, (CH₃)₂ CH--, HOCH₂ --, CH₃ CH(OH)--, (CH₃)₂ C(OH)--, FCH₂ CH(OH)--,F₂ CHCH(OH)--, F₃ CCH(OH)--, CH₃ CH(F)--, CH₃ CF₂ --, or (CH₃)₂C(F)--;R^(a) are independently selected from the group consisting ofhydrogen and the radicals set out below, provided that not more thanfour R^(a) radicals are other than hydrogen:a) a trifluoromethyl group:--CF₃ ; b) a halogen atom: --Br, --Cl, --F, or --I; c) C₁ -C₄ alkoxyradical: --OC₁₋₄ alkyl, wherein the alkyl is optionally mono-substitutedby R^(q), where R^(q) is a member selected from the group consisting of--OH, --OCH₃, --CN, --C(O)NH₂, --OC(O)NH₂, CHO, --OC(O)N(CH₃)₂, --SO₂NH₂, --SO₂ N(CH₃)₂, --SOCH₃, --SO₂ CH₃, --F, --CF₃, --COOM^(a) (whereM^(a) is hydrogen, alkali metal, methyl or phenyl), tetrazolyl (wherethe point of attachment is the carbon atom of the tetrazole ring and oneof the nitrogen atoms is mono-substituted by M^(a) as defined above) and--SO₃ M^(b) (where M^(b) is hydrogen or an alkali metal);d) a hydroxygroup: --OH; e) a carbonyloxy radical: --O(C═O)R^(s), where R^(s) isC₁₋₄ alkyl or phenyl, each of which is optionally mono-substituted byR^(q) as defined above;f) a carbamoyloxy radical: --O(C═O)N(R^(y))R^(z)where R^(y) and R^(z) are independently H, C₁₋₄ alkyl (optionallymono-substituted by R^(q) as defined above), together a 3- to 5-memberedalkylidene radical to form a ring (optionally substituted with R^(q) asdefined above) or together a 2- to 4-membered alkylidene radical,interrupted by --O--, --S--, --S(O)-- or --S(O)₂ -- to form a ring(where the ring is optionally mono-substituted with Rq as definedabove);g) a sulfur radical: --S(O)_(n) --R^(s) where n=0-2, and R^(s) is, defined above; h) a sulfamoyl group: --SO₂ N(R^(y))R^(z) where R^(y)and R^(z) are as defined above; i) azido: N₃ j) a formamido group:--N(R^(t))(C═O)H, where R^(t) is H or C₁₋₄ alkyl, and the alkyl thereofis optionally mono-substituted by R^(q) as defined above;k) a (C₁ -C₄alkyl)carbonylamino radical: --N(R^(t))(C═O)C₁₋₄ alkyl, where R^(t) isas defined above, and the alkyl group is also optionallymono-substituted by R^(q) as defined above; l) a (C₁ -C₄ alkoxy)carbonylamino radical: --N(R^(t))(C═O)OC₁₋₄ alkyl, where R^(t) is asdefined above, and the alkyl group is also optionally mono-substitutedby R^(q) as defined above; m) a ureido group:--N(R^(t))(C═O)N(R^(y))R^(z) where R^(t), R^(y) and R^(z) are as definedabove; n) a sulfonamido group: --N(R^(t))SO₂ R^(s), where R^(s) andR^(t) are as defined above; o) a cyano group: --CN; p) a formyl oracetalized formyl radical: --(C═O)H or --CH(OCH₃)₂ ; q) (C₁ -C₄alkyl)carbonyl radical wherein the carbonyl is acetalized: --C(OCH₃)₂C₁₋₄ alkyl, where the alkyl is optionally mono-substituted by R^(q) asdefined above; r) carbonyl radical: --(C═O)R^(s), where R^(s) is asdefined above; s) a hydroximinomethyl radical in which the oxygen orcarbon atom is optionally substituted by a C₁ -C₄ alkyl group:--(C═NOR^(z))R^(y) where R^(y) and R^(z) are as defined above, exceptthey may not be joined together to form a ring; t) a (C₁ -C₄alkoxy)carbonyl radical: --(C═O)OC₁₋₄ alkyl, where the alkyl isoptionally mono-substituted by R^(q) as defined above; u) a carbamoylradical: --(C═O)N(R^(y))R^(z) where R^(y) and R^(z) are as definedabove; v) an N-hydroxycarbamoyl or N(C₁ -C₄ alkoxy)carbamoyl radical inwhich the nitrogen atom may be additionally substituted by a C₁ -C₄alkyl group: --(C═O)--N(OR^(y))R^(z) where R^(y) and R^(z) are asdefined above, except they may not be joined together to form a ring; w)a thiocarbamoyl group: --(C═S)N(R^(y))(R^(z)) where R^(y) and R^(z) areas defined above; x) carboxyl: --COOM^(b), where M^(b) is as definedabove; y) thiocyanate: --SCN; z) trifluoromethylthio: --SCF₃ ; aa)tetrazolyl, where the point of attachment is the carbon atom of thetetrazole ring and one of the nitrogen atoms is mono-substituted byhydrogen, an alkali metal or a C₁ -C₄ alkyl optionally substituted byR^(q) as defined above; ab) an anionic function selected from the groupconsisting of: phosphono; [P═O(OM^(b))₂ ]; alkylphosphono{P═O(OM^(b))-[O(C₁ -C₄ alkyl)]}; ; alkylphosphinyl; [P═(OM^(b))-(C₁ -C₄alkyl)]; phosphoramido [P═O(OM^(b))N(R^(y))R^(z) and P═O(OM^(b))NHR^(x)]; sulfino (SO₂ M^(b)); sulfo (SO₃ M^(b)); acylsulfonamides selectedfrom the structures CONM^(b) SO₂ R^(x), CONM^(b) SO₂ N(R^(y))R^(z), SO₂NM^(b) CON(R^(y))R^(z) ; and SO₂ NM^(b) CN, where R^(x) i s phenyl orheteroaryl, where heteroaryl is a monocyclic aromatic hydrocarbon grouphaving 5 or 6 ring atoms, in which a carbon atom is the point ofattachment, in which one of the carbon atoms has been replaced by anitrogen atom, in which one additional carbon atom is optionallyreplaced by a heteroatom selected from O or S, and in which from 1 to 2additional carbon atoms are optionally replaced by a nitrogenheteroatom, and where the phenyl and heteroaryl are optionallymono-substituted by R^(q), as defined above; M^(b) is as defined above;and R^(y) and R^(z) are as defined above;ac) C₅ -C₇ cycloalkyl group inwhich one of the carbon atoms in the ring is replaced by a heteroatomselected from O, S, NH or N(C₁ -C₄ alkyl) and in which one additionalcarbon atom may be replaced by NH or N(C₁ -C₄ alkyl), and in which atleast one carbon atom adjacent to each nitrogen heteroatom has both ofits attached hydrogen atoms replaced by one oxygen thus forming acarbonyl moiety and there are one or two carbonyl moieties present inthe ring; ad) C₂ -C₄ alkenyl radical, optionally mono-substituted by oneof the substituents a) to ac) above and phenyl which is optionallysubstituted by R^(q) as defined above; ae) C₂ -C₄ alkynyl radical,optionally mono-substituted by one of the substituents a) to ac) above;af) C₁ -C₄ alkyl radical; ag) C₁ -C₄ alkyl mono-substituted by one ofthe substituents a)-ac) above; ah) a 2-oxazolidinonyl moiety in whichthe point of attachment is the nitrogen atom of the oxazolidinone ring,the ring oxygen atom is optionally replaced by a heteroatom selectedfrom --S-- and NR^(t) (where R^(t) is as defined above) and one of thesaturated carbon atoms of the oxazolidinone ring is optionallymono-substituted by one of the substituents a) to ag) above; ai) anamine group: --NR^(e) R^(f), where R^(e) and R^(f) are independently H,C₁₋₄ alkyl (optionally mono-substituted by R^(q) as defined above),together a 4- to 5-membered alkylidene radical to form a ring(optionally substituted with R^(q) as defined above); R^(c) is selectedfrom the group consisting of hydrogen and the radicals set out below:ba)C₁ -C₄ alkyl radical; bb) C₁ -C₄ alkyl mono-substituted by one of thesubstituents a)-ac) described hereinabove; bc) C₁ -C₄ alkoxy radical:--OC₁₋₄ alkyl, wherein the alkyl is optionally mono-substituted byR^(q), where R^(q) is as described hereinabove; and bd) an amine group:--NR^(g) R^(h), where R^(g) and R^(h) are independently H, C₁₋₄ alkyl(optionally mono-substituted by R^(q) as defined above), together a 4-to 5-membered alkylidene radical to form a ring (optionally substitutedwith R^(q) as defined above) or R^(g) is combined with R^(d) to form adiradical selected from the group consisting of: --CH₂ CH₂ --, --CH₂ CH₂CH₂ -- and --CH═CH--; R^(d) is --NH₂, --O⁻, C₁ -C₄ -alkyl (where thealkyl group is optionally monosubstituted with R^(q) as defined above),or hydrogen, or R^(d) is combined with R^(g) to form a diradicalselected from the group consisting of: --CH₂ CH₂ --, --CH₂ CH₂ CH₂ --and --CH═CH--; provided that R^(d) is hydrogen only if at least oneR^(a) or R^(c) is an amine group;m is 0 to 1, if at least one R^(a) orR^(c) is an amine group; m is 1 if neither R^(a) nor R^(c) is an aminegroup; and M is selected from:i) hydrogen; ii) a pharmaceuticallyacceptable esterifying group or removable carboxyl protecting group;iii) an alkali metal or other pharmaceutically acceptable cation; or(iv) a negative charge.
 2. The compound of claim 1, wherein R¹ ishydrogen and R² is (R)--CH₃ CH(OH)-- or (R)--CH₃ CH(F)--.
 3. Thecompound according to claim 1 wherein:R^(g) and R^(h) are independentlyH, C₁₋₄ alkyl (optionally mono-substituted by R^(q) as defined above) ortogether are a 4- to 5-membered alkylidene radical forming a ring(optionally substituted with R^(q) as defined above); and R^(d) is--NH₂, --O⁻, C₁ -C₄ -alkyl (where the alkyl group is optionallymonosubstituted with R^(q) as defined above), or hydrogen;provided thatR^(d) is hydrogen only if at least one R^(a) or R^(c) is an amine group.4. The compound according to claim 1 wherein:Y= ##STR64##
 5. Thecompound according to claim 1 wherein:Y= ##STR65##
 6. The compoundaccording to claim 1, wherein the structural formula is: ##STR66## andthe substituents R^(a') (which is R^(a) when it is not hydrogen), R,R^(c), R^(d) and T are as defined in Table I below:

                                      TABLE I                                     __________________________________________________________________________                    R.sup.a '                                                     R  R.sup.a '    Position                                                                           T  R.sup.c   R.sup.d                                     __________________________________________________________________________    H  --CN         4    OH H         CH.sub.3                                    H  --CONH.sub.2 4    OH H         CH.sub.3                                    H  --CONMe.sub.2                                                                              4    OH H         CH.sub.3                                    H  --CHO        4    OH H         CH.sub.3                                    H  --SCH.sub.3  4    OH H         CH.sub.3                                    H  --SOCH.sub.3 4    OH H         CH.sub.3                                    H  --SO.sub.2 CH.sub.3                                                                        4    OH H         CH.sub.3                                    H  --F          4    OH H         CH.sub.3                                    H  --SO.sub.2 NH.sub.2                                                                        4    OH H         CH.sub.3                                    H  --CH.sub.2 OH                                                                              8    OH H         CH.sub.3                                    H  --CN         8    OH H         CH.sub.3                                    H  --CONH.sub.2 8    OH H         CH.sub.3                                    H  --CHO        8    OH H         CH.sub.3                                    H  --CH.sub.2 OH                                                                              7    OH H         CH.sub.3                                    H  --CN         7    OH H         CH.sub.3                                    H  --CONH.sub.2 7    OH H         CH.sub.3                                    H  --CHO        7    OH H         CH.sub.3                                    H  --CN         4    F  H         CH.sub.3                                    H  --CHO        4    F  H         CH.sub.3                                    H  --CONH.sub.2 4    F  H         CH.sub.3                                    CH.sub.3                                                                         --CN         4    OH H         CH.sub.3                                    CH.sub.3                                                                         --CONH.sub.2 4    OH H         CH.sub.3                                    CH.sub.3                                                                         --CHO        4    OH H         CH.sub.3                                    CH.sub.3                                                                         --CN         4    F  H         CH.sub.3                                    H  --CN         4    OH H         Et                                          H  --CONH.sub.2 4    OH H         Pr                                          H  --CONH.sub.2 4    OH H         Bu                                          H  --CF.sub.3   8    OH H         CH.sub.3                                    H  --OCH.sub.3  9    OH H         CH.sub.3                                    H  --OCH.sub.2 CO.sub.2 CH.sub.3                                                              10   OH H         CH.sub.3                                    H  --Cl         4, 7, 8                                                                            OH H         CH.sub.3                                    H  --OH         9    OH H         CH.sub.3                                    H  --OCOCH.sub.3                                                                              8    OH H         CH.sub.3                                    H  --OCONH.sub.2                                                                              8    OH H         CH.sub.3                                    H  --SCH.sub.2 CH.sub.2 OH                                                                    8    OH H         CH.sub.3                                    H  --SOCH.sub.2 CH.sub.2 OH                                                                   9    OH H         CH.sub.3                                    H  --SCH.sub.2 CONH.sub.2                                                                     4    OH H         CH.sub.3                                    H  --SO.sub.2 NMe.sub.2                                                                       4, 8 OH H         CH.sub.3                                    H  --NHCHO      8    OH H         CH.sub.3                                    H  --                OH --NHCH.sub.2 CONH.sub.2                                                                 CH.sub.3                                    H  --                OH --N(CH.sub.3).sub.2                                                                     CH.sub.3                                    H  --                F  --N(CH.sub.3).sub.2                                                                     CH.sub.3                                    CH.sub.3                                                                         --                OH --N(CH.sub.3).sub.2                                                                     CH.sub.3                                    H  --CH.sub.2 OH                                                                              8    OH H         O.sup.-                                     H  --CH.sub.2 OH                                                                              8    OH H         NH.sub.2                                    H  --CH.sub.2 OH                                                                              8    OH H         CH.sub.2 CH.sub.2 OH                        H  --CH.sub.2 OH                                                                              8    OH H         CH.sub.2 CH.sub.2 CH.sub.2 CN               H  --NHCOCH.sub.3                                                                             9    OH H         CH.sub.3                                    H  --NHCOCH.sub.3                                                                             10   OH H         CH.sub.3                                    H  --NHSO.sub.2 CH.sub.3                                                                      4    OH H         CH.sub.3                                    H  --COMe       4    OH H         CH.sub.3                                    H  --COCH.sub.2 OH                                                                            7    OH H         CH.sub.3                                    H  --CH═NOH 8    OH H         CH.sub.3                                    H  --CH═NOMe                                                                              7    OH H         CH.sub.3                                    H  --CH═NOCH.sub.2 CO.sub.2 Me                                                            8    OH H         CH.sub.3                                    H  --CH═NOCMe.sub.2 CO.sub.2 Me                                                           8    OH H         CH.sub.3                                    H  --CH═NOCMe.sub.2 CONH.sub.2                                                            9    OH H         CH.sub.3                                    H  --CO.sub.2 CH.sub.2 CH.sub.2 OH                                                            10   OH H         CH.sub.3                                    H  --CONHCH.sub.3                                                                             4    OH H         CH.sub.3                                    H  --CONHCH.sub.2 CN                                                                          4    OH H         CH.sub.3                                    H  --CONHCH.sub.2 CN                                                                          4    F  H         CH.sub.3                                    CH.sub.3                                                                         --CONHCH.sub.2 CN                                                                          4    OH H         CH.sub.3                                    H  --CONHCH.sub.2 CONH.sub.2                                                                  8    OH H         CH.sub.3                                    H  --CONHCH.sub.2 CO.sub.2 CH.sub.3                                                           9    OH H         CH.sub.3                                    H  --CONHOH     4    OH H         CH.sub.3                                    H  --CONHOCH.sub.3                                                                            10   OH H         CH.sub.3                                    H  --CO.sub.2 CH.sub.3                                                                        4    OH H         CH.sub.3                                    tetrazolyl                                                                       8            OH   H  CH.sub.3                                              H  --SCF.sub.3  4    OH H         CH.sub.3                                    H  --PO.sub.2 NH.sub.2                                                                        4    OH H         CH.sub.3                                    H  --CONHSO.sub.2 Ph                                                                          4    OH H         CH.sub.3                                    H  --CONHSO.sub.2 NH.sub.2                                                                    4    OH H         CH.sub.3                                    H  --SO.sub.2 CF.sub.3                                                                        8    OH H         CH.sub.3                                    H  --SO.sub.2 NHCN                                                                            4    OH H         CH.sub.3                                    H  --SO.sub.2 NHCONH.sub.2                                                                    4    OH H         CH.sub.3                                    H  --CH═CHCN                                                                              4    OH H         CH.sub.3                                    H  --CH═CHCONH.sub.2                                                                      4    OH H         CH.sub. 3                                   H  --C═C--CN                                                                              4    OH H         CH.sub.3                                    H  --CH.sub.2 N.sub.3                                                                         7    OH H         CH.sub.3                                    H  --CH.sub.2 CO.sub.2 Me                                                                     10   OH H         CH.sub.3                                    H  --SO.sub.2 CH.sub.2 CH.sub.2 OH                                                            4    OH H         CH.sub.3                                    H  --CH.sub.2 I 8    OH H         CH.sub.3                                    H  --I          4    OH H         CH.sub.3                                    H  --Br         4    OH H         CH.sub.3                                    H  --                OH H         CH.sub.2 CH.sub.2 CH.sub.3                  H  --                OH OCH.sub.3 CH.sub.3                                    H  --                OH NHCH.sub.2 CH.sub.2 OH                                                                  CH.sub.3                                    H  --                OH N-pyrrolidinyl                                                                          CH.sub.3 or                                 H  --                OH NH.sub.2  H.                                          __________________________________________________________________________


7. The compound according to claim 1, wherein the structural formula is:##STR67## and the substituents R^(a') (which is R^(a) when it is nothydrogen), R, R^(c), R^(d) and T are as defined in Table II below:

                                      TABLE II                                    __________________________________________________________________________                    R.sup.a '                                                     R  R.sup.a '    Position                                                                           T  R.sup.c   R.sup.d                                     __________________________________________________________________________    H  --CN         7    OH H         CH.sub.3                                    H  --CONH.sub.2 7    OH H         CH.sub.3                                    H  --CONMe.sub.2                                                                              7    OH H         CH.sub.3                                    H  --CHO        7    OH H         CH.sub.3                                    H  --SCH.sub.3  7    OH H         CH.sub.3                                    H  --SOCH.sub.3 7    OH H         CH.sub.3                                    H  --SO.sub.2 CH.sub.3                                                                        7    OH H         CH.sub.3                                    H  --F          7    OH H         CH.sub.3                                    H  --SO.sub.2 NH.sub.2                                                                        7    OH H         CH.sub.3                                    H  --CH.sub.2 OH                                                                              3    OH H         CH.sub.3                                    H  --CN         3    OH H         CH.sub.3                                    H  --CONH.sub.2 3    OH H         CH.sub.3                                    H  --CHO        3    OH H         CH.sub.3                                    H  --CH.sub.2 OH                                                                              4    OH H         CH.sub.3                                    H  --CN         4    OH H         CH.sub.3                                    H  --CONH.sub.2 4    OH H         CH.sub.3                                    H  --CHO        4    OH H         CH.sub.3                                    H  --CN         7    F  H         CH.sub.3                                    H  --CHO        7    F  H         CH.sub.3                                    H  --CONH.sub.2 7    F  H         CH.sub.3                                    CH.sub.3                                                                         --CN         7    OH H         CH.sub.3                                    CH.sub.3                                                                         --CONH.sub.2 7    OH H         CH.sub.3                                    CH.sub.3                                                                         --CHO        7    OH H         CH.sub.3                                    CH.sub.3                                                                         --CN         7    F  H         CH.sub.3                                    H  --CN         7    OH H         Et                                          H  --CONH.sub.2 7    OH H         Pr                                          H  --CONH.sub.2 7    OH H         Bu                                          H  --CF.sub.3   3    OH H         CH.sub.3                                    H  --OCH.sub.3  2    OH H         CH.sub.3                                    H  --OCH.sub.2 CO.sub.2 CH.sub.3                                                              1    OH H         CH.sub.3                                    H  --Cl         3, 4, 7                                                                            OH H         CH.sub.3                                    H  --OH         2    OH H         CH.sub.3                                    H  --OCOCH.sub.3                                                                              3    OH H         CH.sub.3                                    H  --OCONH.sub.2                                                                              3    OH H         CH.sub.3                                    H  --SCH.sub.2 CH.sub.2 OH                                                                    3    OH H         CH.sub.3                                    H  --SOCH.sub.2 CH.sub.2 OH                                                                   2    OH H         CH.sub.3                                    H  --SCH.sub.2 CONH.sub.2                                                                     7    OH H         CH.sub.3                                    H  --SO.sub.2 NMe.sub.2                                                                       7, 3 OH H         CH.sub.3                                    H  --NHCHO      3    OH H         CH.sub.3                                    H  --                OH --NHCH.sub. 2 CONH.sub.2                                                                CH.sub.3                                    H  --                OH --N(CH.sub.3).sub.2                                                                     CH.sub.3                                    H  --                F  --N(CH.sub.3).sub.2                                                                     CH.sub.3                                    CH.sub.3                                                                         --                OH --N(CH.sub.3).sub.2                                                                     CH.sub.3                                    H  --CH.sub.2 OH                                                                              3    OH H         O.sup.-                                     H  --CH.sub.2 OH                                                                              3    OH H         NH.sub.2                                    H  --CH.sub.2 OH                                                                              3    OH H         CH.sub.2 CH.sub.2 OH                        H  --CH.sub.2 OH                                                                              3    OH H         CH.sub.2 CH.sub.2 CH.sub.2 CN               H  --NHCOCH.sub.3                                                                             2    OH H         CH.sub.3                                    H  --NHCOCH.sub.3                                                                             1    OH H         CH.sub.3                                    H  --NHSO.sub.2 CH.sub.3                                                                      7    OH H         CH.sub.3                                    H  --COMe       7    OH H         CH.sub.3                                    H  --COCH.sub.2 OH                                                                            4    OH H         CH.sub.3                                    H  --CH═NOH 3    OH H         CH.sub.3                                    H  --CH═NOMe                                                                              4    OH H         CH.sub.3                                    H  --CH═NOCH.sub.2 CO.sub.2 Me                                                            3    OH H         CH.sub.3                                    H  --CH═NOCMe.sub.2 CO.sub.2 Me                                                           3    OH H         CH.sub.3                                    H  --CH═NOCMe.sub.2 CONH.sub.2                                                            2    OH H         CH.sub.3                                    H  --CO.sub.2 CH.sub.2 CH.sub.2 OH                                                            1    OH H         CH.sub.3                                    H  --CONHCH.sub.3                                                                             7    OH H         CH.sub.3                                    H  --CONHCH.sub.2 CN                                                                          7    OH H         CH.sub.3                                    H  --CONHCH.sub.2 CN                                                                          7    F  H         CH.sub.3                                    CH.sub.3                                                                         --CONHCH.sub.2 CN                                                                          7    OH H         CH.sub.3                                    H  --CONHCH.sub.2 CONH.sub.2                                                                  3    OH H         CH.sub.3                                    H  --CONHCH.sub.2 CO.sub.2 CH.sub.3                                                           2    OH H         CH.sub.3                                    H  --CONHOH     7    OH H         CH.sub.3                                    H  --CONHOCH.sub.3                                                                            1    OH H         CH.sub.3                                    H  --CO.sub.2 CH.sub.3                                                                        7    OH H         CH.sub.3                                    tetrazolyl                                                                       3            OH   H  CH.sub.3                                              H  --SCF.sub.3  7    OH H         CH.sub.3                                    H  --PO.sub.2 NH.sub.2                                                                        7    OH H         CH.sub.3                                    H  --CONHSO.sub.2 Ph                                                                          7    OH H         CH.sub.3                                    H  --CONHSO.sub.2 NH.sub.2                                                                    7    OH H         CH.sub.3                                    H  --SO.sub.2 CF.sub.3                                                                        3    OH H         CH.sub.3                                    H  --SO.sub.2 NHCN                                                                            7    OH H         CH.sub.3                                    H  --SO.sub.2 NHCONH.sub.2                                                                    7    OH H         CH.sub.3                                    H  --CH═CHCN                                                                              7    OH H         CH.sub.3                                    H  --CH═CHCONH.sub.2                                                                      7    OH H         CH.sub.3                                    H  --C═C--CN                                                                              7    OH H         CH.sub.3                                    H  --CH.sub.2 N.sub.3                                                                         4    OH H         CH.sub.3                                    H  --CH.sub.2 CO.sub.2 Me                                                                     1    OH H         CH.sub.3                                    H  --SO.sub.2 CH.sub.2 CH.sub.2 OH                                                            7    OH H         CH.sub.3                                    H  --CH.sub.2 I 3    OH H         CH.sub.3                                    H  --I          7    OH H         CH.sub.3                                    H  --Br         7    OH H         CH.sub.3                                    H  --                OH H         CH.sub.2 CH.sub.2 CH.sub.3                  H  --                OH OCH.sub.3 CH.sub.3                                    H  --                OH NHCH.sub.2 CH.sub.2 OH                                                                  CH.sub.3                                    H  --                OH N-pyrrolidinyl                                                                          CH.sub.3 or                                 H  --                OH NH.sub.2  H.                                          __________________________________________________________________________


8. The compound according to claim 1, wherein the structural formula is:##STR68## and the substituents R^(a') (which is R^(a) when it is nothydrogen), R, R^(c), R^(d) and T are as defined in Table III below:

                                      TABLE III                                   __________________________________________________________________________                    R.sup.a'                                                      R  R.sup.a'     Position                                                                           T  R.sup.c  R.sup.d                                      __________________________________________________________________________    H  --CN         1    OH H        CH.sub.3                                     H  --CONH.sub.2 1    OH H        CH.sub.3                                     H  --CONMe.sub.2                                                                              1    OH H        CH.sub.3                                     H  --CHO        1    OH H        CH.sub.3                                     H  --SCH.sub.3  1    OH H        CH.sub.3                                     H  --SOCH.sub.3 1    OH H        CH.sub.3                                     H  --SO.sub.2 CH.sub.3                                                                        1    OH H        CH.sub.3                                     H  --F          1    OH H        CH.sub.3                                     H  --SO.sub.2 NH.sub.2                                                                        1    OH H        CH.sub.3                                     H  --CH.sub.2 OH                                                                              8    OH H        CH.sub.3                                     H  --CN         8    OH H        CH.sub.3                                     H  --CONH.sub.2 8    OH H        CH.sub.3                                     H  --CHO        8    OH H        CH.sub.3                                     H  --CH.sub.2 OH                                                                              7    OH H        CH.sub.3                                     H  --CN         7    OH H        CH.sub.3                                     H  --CONH.sub.2 7    OH H        CH.sub.3                                     H  --CHO        7    OH H        CH.sub.3                                     H  --CN         1    F  H        CH.sub.3                                     H  --CHO        1    F  H        CH.sub.3                                     H  --CONH.sub.2 1    F  H        CH.sub.3                                     CH.sub.3                                                                         --CN         1    OH H        CH.sub.3                                     CH.sub.3                                                                         --CONH.sub.2 1    OH H        CH.sub.3                                     CH.sub.3                                                                         --CHO        1    OH H        CH.sub.3                                     CH.sub.3                                                                         --CN         1    F  H        CH.sub.3                                     H  --CN         1    OH H        Et                                           H  --CONH.sub.2 1    OH H        Pr                                           H  --CONH.sub.2 1    OH H        Bu                                           H  --CF.sub.3   8    OH H        CH.sub.3                                     H  --OCH.sub.3  9    OH H        CH.sub.3                                     H  --OCH.sub.2 CO.sub.2 CH.sub.3                                                              10   OH H        CH.sub.3                                     H  --Cl         1,7,8                                                                              OH H        CH.sub.3                                     H  --OH         9    OH H        CH.sub.3                                     H  --OCOCH.sub.3                                                                              8    OH H        CH.sub.3                                     H  --OCONH.sub.2                                                                              8    OH H        CH.sub.3                                     H  --SCH.sub.2 CH.sub.2 OH                                                                    8    OH H        CH.sub.3                                     H  --SOCH.sub.2 CH.sub.2 OH                                                                   9    OH H        CH.sub.3                                     H  --SCH.sub.2 CONH.sub.2                                                                     1    OH H        CH.sub.3                                     H  --SO.sub.2 NMe.sub.2                                                                       1,8  OH H        CH.sub.3                                     H  --NHCHO      8    OH H        CH.sub.3                                     H  --                OH --NHCH.sub.2 CONH.sub.2                                                                CH.sub.3                                     H  --                OH --N(CH.sub.3).sub.2                                                                    CH.sub.3                                     H  --                F  --N(CH.sub.3).sub.2                                                                    CH.sub.3                                     CH.sub.3                                                                         --                OH --N(CH.sub.3).sub.2                                                                    CH.sub.3                                     H  --CH.sub.2 OH                                                                              8    OH H        O.sup.-                                      H  --CH.sub.2 OH                                                                              8    OH H        NH.sub.2                                     H  --CH.sub.2 OH                                                                              8    OH H        CH.sub.2 CH.sub.2 OH                         H  --CH.sub.2 OH                                                                              8    OH H        CH.sub.2 CH.sub.2 CH.sub.2 CN                H  --NHCOCH.sub.3                                                                             9    OH H        CH.sub.3                                     H  --NHCOCH.sub.3                                                                             10   OH H        CH.sub.3                                     H  --NHSO.sub.2 CH.sub.3                                                                      1    OH H        CH.sub.3                                     H  --COMe       1    OH H        CH.sub.3                                     H  --COCH.sub.2 OH                                                                            7    OH H        CH.sub.3                                     H  --CH═NOH 8    OH H        CH.sub.3                                     H  --CH═NOMe                                                                              7    OH H        CH.sub.3                                     H  --CH═NOCH.sub.2 CO.sub.2 Me                                                            8    OH H        CH.sub.3                                     H  --CH═NOCM.sub.e2 CO.sub.2 Me                                                           8    OH H        CH.sub.3                                     H  --CH═NOCMe.sub.2 CONH.sub.2                                                            9    OH H        CH.sub.3                                     H  --CO.sub.2 CH.sub.2 CH.sub.2 OH                                                            10   OH H        CH.sub.3                                     H  --CONHCH.sub.3                                                                             1    OH H        CH.sub.3                                     H  --CONHCH.sub.2 CN                                                                          1    OH H        CH.sub.3                                     H  --CONHCH.sub.2 CN                                                                          1    F  H        CH.sub.3                                     CH.sub.3                                                                         --CONHCH.sub.2 CN                                                                          1    OH H        CH.sub.3                                     H  --CONHCH.sub.2 CONH.sub.2                                                                  8    OH H        CH.sub.3                                     H  --CONHCH.sub.2 CO.sub.2 CH.sub.3                                                           9    OH H        CH.sub.3                                     H  --CONHOH     1    OH H        CH.sub.3                                     H  --CONHOCH.sub.3                                                                            10   OH H        CH.sub.3                                     H  --CO.sub.2 CH.sub.3                                                                        1    OH H        CH.sub.3                                     tetrazolyl                                                                       8            OH   H  CH.sub.3                                              H  --SCF.sub.3  1    OH H        CH.sub.3                                     H  --PO.sub.2 NH.sub.2                                                                        1    OH H        CH.sub.3                                     H  --CONHSO.sub.2 Ph                                                                          1    OH H        CH.sub.3                                     H  --CONHSO.sub.2 NH.sub.2                                                                    1    OH H        CH.sub.3                                     H  --SO.sub.2 CF.sub.3                                                                        8    OH H        CH.sub.3                                     H  --SO.sub.2 NHCN                                                                            1    OH H        CH.sub.3                                     H  --SO.sub.2 NHCONH.sub.2                                                                    1    OH H        CH.sub.3                                     H  --CH═CHCN                                                                              1    OH H        CH.sub.3                                     H  --CH═CHCONH.sub.2                                                                      1    OH H        CH.sub.3                                     H  --C═C-- CN                                                                             1    OH H        CH.sub.3                                     H  --CH.sub.2 N.sub.3                                                                         7    OH H        CH.sub.3                                     H  --CH.sub.2 CO.sub.2 Me                                                                     10   OH H        CH.sub.3                                     H  --SO.sub.2 CH.sub.2 CH.sub.2 OH                                                            1    OH H        CH.sub.3                                     H  --CH.sub.2 I 8    OH H        CH.sub.3                                     H  --I          1    OH H        CH.sub.3                                     H  --Br         1    OH H        CH.sub.3                                     H  --                OH H        CH.sub.2 CH.sub.2 CH.sub.3                   H  --                OH OCH.sub.3                                                                              CH.sub.3                                     H  --                OH NHCH.sub.2 CH.sub.2 OH                                                                 CH.sub.3                                     H  --                OH N-pyrrol-                                                                              CH.sub.3 or                                                          idinyl                                                H  --                OH NH.sub.2 H.                                           __________________________________________________________________________


9. The compound according to claim 1, wherein the structural formula is:##STR69## and the substituents R^(a') (which is R^(a) when it is nothydrogen), R, R^(c), R^(d) and T are as defined in Table IV below:

                                      TABLE IV                                    __________________________________________________________________________                    R.sup.a'                                                      R  R.sup.a'     Position                                                                           T  R.sup.c  R.sup.d                                      __________________________________________________________________________    H  --CN         7    OH H        CH.sub.3                                     H  --CONH.sub.2 10   OH H        CH.sub.3                                     H  --CONMe.sub.2                                                                              10   OH H        CH.sub.3                                     H  --CHO        10   OH H        CH.sub.3                                     H  --SCH.sub.3  10   OH H        CH.sub.3                                     H  --SOCH.sub.3 10   OH H        CH.sub.3                                     H  --SO.sub.2 CH.sub.3                                                                        10   OH H        CH.sub.3                                     H  --F          10   OH H        CH.sub.3                                     H  --SO.sub.2 NH.sub.2                                                                        10   OH H        CH.sub.3                                     H  --CH.sub.2 OH                                                                              3    OH H        CH.sub.3                                     H  --CN         3    OH H        CH.sub.3                                     H  --CONH.sub.2 3    OH H        CH.sub.3                                     H  --CHO        3    OH H        CH.sub.3                                     H  --CH.sub.2 OH                                                                              4    OH H        CH.sub.3                                     H  --CN         4    OH H        CH.sub.3                                     H  --CONH.sub.2 4    OH H        CH.sub.3                                     H  --CHO        4    OH H        CH.sub.3                                     H  --CN         10   F  H        CH.sub.3                                     H  --CHO        10   F  H        CH.sub.3                                     H  --CONH.sub.2 10   F  H        CH.sub.3                                     CH.sub.3                                                                         --CN         10   OH H        CH.sub.3                                     CH.sub.3                                                                         --CONH.sub.2 10   OH H        CH.sub.3                                     CH.sub.3                                                                         --CHO        10   OH H        CH.sub.3                                     CH.sub.3                                                                         --CN         10   F  H        CH.sub.3                                     H  --CN         10   OH H        Et                                           H  --CONH.sub.2 10   OH H        Pr                                           H  --CONH.sub.2 10   OH H        Bu                                           H  --CF.sub.3   3    OH H        CH.sub.3                                     H  --OCH.sub.3  2    OH H        CH.sub.3                                     H  --OCH.sub.2 CO.sub.2 CH.sub.3                                                              1    OH H        CH.sub.3                                     H  --Cl         3,4,10                                                                             OH H        CH.sub.3                                     H  --OH         2    OH H        CH.sub.3                                     H  --OCOCH.sub.3                                                                              3    OH H        CH.sub.3                                     H  --OCONH.sub.2                                                                              3    OH H        CH.sub.3                                     H  --SCH.sub.2 CH.sub.2 OH                                                                    3    OH H        CH.sub.3                                     H  --SOCH.sub.2 CH.sub.2 OH                                                                   2    OH H        CH.sub.3                                     H  --SCH.sub.2 CONH.sub.2                                                                     10   OH H        CH.sub.3                                     H  --SO.sub.2 NMe.sub.2                                                                       10,3 OH H        CH.sub.3                                     H  --NHCHO      3    OH H        CH.sub.3                                     H  --                OH --NHCH.sub.2 CONH.sub.2                                                                CH.sub.3                                     H  --                OH --N(CH.sub.3).sub.2                                                                    CH.sub.3                                     H  --                F  --N(CH.sub.3).sub.2                                                                    CH.sub.3                                     CH.sub.3                                                                         --                OH --N(CH.sub.3).sub.2                                                                    CH.sub.3                                     H  --CH.sub.2 OH                                                                              3    OH H        O.sup.-                                      H  --CH.sub.2 OH                                                                              3    OH H        NH.sub.2                                     H  --CH.sub.2 OH                                                                              3    OH H        CH.sub.2 CH.sub.2 OH                         H  --CH.sub.2 OH                                                                              3    OH H        CH.sub.2 CH.sub.2 CH.sub.2 CN                H  --NHCOCH.sub.3                                                                             2    OH H        CH.sub.3                                     H  --NHCOCH.sub.3                                                                             1    OH H        CH.sub.3                                     H  --NHSO.sub.2 CH.sub.3                                                                      10   OH H        CH.sub.3                                     H  --COMe       10   OH H        CH.sub.3                                     H  --COCH.sub.2 OH                                                                            4    OH H        CH.sub.3                                     H  --CH═NOH 3    OH H        CH.sub.3                                     H  --CH═NOMe                                                                              4    OH H        CH.sub.3                                     H  --CH═NOCH.sub.2 CO.sub.2 Me                                                            3    OH H        CH.sub.3                                     H  --C═NOCM.sub.e2 CO.sub.2 Me                                                            3    OH H        CH.sub.3                                     H  --CH═NOCMe.sub.2 CONH.sub.2                                                            2    OH H        CH.sub.3                                     H  --CO.sub.2 CH.sub.2 CH.sub.2 OH                                                            1    OH H        CH.sub.3                                     H  --CONHCH.sub.3                                                                             10   OH H        CH.sub.3                                     H  --CONHCH.sub.2 CN                                                                          10   OH H        CH.sub.3                                     H  --CONHCH.sub.2 CN                                                                          10   F  H        CH.sub.3                                     CH.sub.3                                                                         --CONHCH.sub.2 CN                                                                          10   OH H        CH.sub.3                                     H  --CONHCH.sub.2 CONH.sub.2                                                                  3    OH H        CH.sub.3                                     H  --CONHCH.sub.2 CO.sub.2 CH.sub.3                                                           2    OH H        CH.sub.3                                     H  --CONHOH     10   OH H        CH.sub.3                                     H  --CONHOCH.sub.3                                                                            1    OH H        CH.sub.3                                     H  --CO.sub.2 CH.sub.3                                                                        10   OH H        CH.sub.3                                     tetrazolyl                                                                       3            OH   H  CH.sub.3                                              H  --SCF.sub.3  10   OB H        CH.sub.3                                     H  --PO.sub.2 NH.sub.2                                                                        10   OH H        CH.sub.3                                     H  --CONHSO.sub.2 Ph                                                                          10   OH H        CH.sub.3                                     H  --CONHSO.sub.2 NH.sub.2                                                                    10   OH H        CH.sub.3                                     H  --SO.sub.2 CF.sub.3                                                                        3    OH H        CH.sub.3                                     H  --SO.sub.2 NHCN                                                                            10   OH H        CH.sub.3                                     H  --SO.sub.2 NHCONH.sub.2                                                                    10   OH H        CH.sub.3                                     H  --CH═CHCN                                                                              10   OH H        CH.sub.3                                     H  --CH═CHCONH.sub.2                                                                      10   OH H        CH.sub.3                                     H  --C═C-- CN                                                                             10   OH H        CH.sub.3                                     H  --CH.sub.2 N.sub.3                                                                         4    OH H        CH.sub.3                                     H  --CH.sub.2 CO.sub.2 Me                                                                     1    OH H        CH.sub.3                                     H  --SO.sub.2 CH.sub.2 CH.sub.2 OH                                                            10   OH H        CH.sub.3                                     H  --CH.sub.2 I 3    OH H        CH.sub.3                                     H  --I          10   OH H        CH.sub.3                                     H  --Br         10   OH H        CH.sub.3                                     H  --                OH H        CH.sub.2 CH.sub.2 CH.sub.3                   H  --                OH OCH.sub.3                                                                              CH.sub.3                                     H  --                OH NHCH.sub.2 CH.sub.2 OH                                                                 CH.sub.3                                     H  --                OH N-pyrrol-                                                                              CH.sub.3 or                                                          idinyl                                                H  --                OH NH.sub.2 H.                                           __________________________________________________________________________


10. A compound according to claim 4 wherein the structural formula is:##STR70## and the R^(a) substituent is selected from CH₂ OH, CO₂ CH₃,CONH₂, Cl, CN, CHO, SCH₃, SCH₂ CH₂ OH and SO₂ CH₃.
 11. A compoundaccording to claim 5 wherein the structural formula is: ##STR71## andthe R^(a) substituent is selected from CH₂ OH, CO₂ CH₃, CONH₂, Cl, CN,CHO, SCH₃, SCH₂ CH₂ OH and SO₂ CH₃.
 12. A compound according to claim 1wherein the structural formula is: ##STR72##
 13. A compound according toclaim 1 wherein the structural formula is: ##STR73##
 14. Apharmaceutical composition for antibacterial use comprising anantibacterially effective amount of a compound of claim 1 and apharmaceutically acceptable carrier.
 15. A method of treating bacterialinfections in human or animal subjects in need of such treatmentcomprising administering to such subject an antibacterially effectiveamount of a compound of claim
 1. 16. A pharmaceutical composition forantibacterial use comprising an antibacterially effective amount of acompound of claim 1, an inhibitorily effective amount of adehydropeptidase (DHP) inhibitor, and optionally, a pharmaceuticallyacceptable carrier.
 17. A pharmaceutical composition according to claim16, wherein the DHP inhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoicacid.
 18. A method of treating bacterial infections in human or animalsubjects in need of such treatment comprising coadministering to suchsubject an antibacterially effective amount of a compound of claim 1 andan inhibitorily effective amount of a DHP inhibitor.
 19. The methodaccording to claim 18, wherein the DHP inhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2heptenoicacid.